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Shen Y, Li J, Zhao Z, Chen X. Progress on long non-coding RNAs in calcific aortic valve disease. Front Cardiovasc Med 2025; 12:1522544. [PMID: 39898106 PMCID: PMC11782120 DOI: 10.3389/fcvm.2025.1522544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/02/2025] [Indexed: 02/04/2025] Open
Abstract
Calcific aortic valve disease (CAVD) is a common cardiovascular condition in the elderly population. The aortic valve, influenced by factors such as endothelial dysfunction, inflammation, oxidative stress, lipid metabolism disorders, calcium deposition, and extracellular matrix remodeling, undergoes fibrosis and calcification, ultimately leading to stenosis. In recent years, long non-coding RNAs (lncRNAs) have emerged as significant regulators of gene expression, playing crucial roles in the occurrence and progression of various diseases. Research has shown that lncRNAs participate in the pathological process underlying CAVD by regulating osteogenic differentiation and inflammatory response of valve interstitial cells. Specifically, lncRNAs, such as H19, MALAT1, and TUG1, are closely associated with CAVD. Some lncRNAs can act as miRNA sponges, form complex regulatory networks, and modulate the expression of calcification-related genes. In brief, this review discusses the mechanisms and potential therapeutic targets of lncRNAs in CAVD.
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Affiliation(s)
- Yan Shen
- Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Jiahui Li
- Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Zehao Zhao
- Department of Cardiology, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Xiaomin Chen
- Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China
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Yang Y, Gao N, Ji G, Hu W, Bi R, Liang J, Liu Y. Static magnetic field contributes to osteogenic differentiation of hPDLSCs through the H19/Wnt/β-catenin axis. Gene 2025; 933:148967. [PMID: 39341520 DOI: 10.1016/j.gene.2024.148967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 09/05/2024] [Accepted: 09/24/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Static magnetic field (SMF) as an effective physical stimulus is capable of osteogenic differentiation for multiple mesenchymal stem cells, including human periodontal ligament stem cells (hPDLSCs). However, the exact molecular mechanism is still unknown. Therefore, this study intends to excavate molecular mechanisms related to SMF in hPDLSCs using functional experiments. METHODS hPDLSCs were treated with different intensities of SMF, H19 lentivirus, and Wnt/β-catenin pathway inhibitor (XAV939). Changes in osteogenic markers (Runx2, Col Ⅰ, and BMP2), Wnt/β-catenin markers (β-catenin and GSK-3β), and calcified nodules were examined using RT-qPCR, western blotting, and alizarin red staining in hPDLSCs. RESULTS SMF upregulated the expression of H19, and SMF and overexpressing H19 facilitated the expression of osteogenic markers (Runx2, Col Ⅰ, and BMP2), activation of the Wnt/β-catenin pathway, and mineralized sediment in hPDLSCs. Knockdown of H19 alleviated SMF function, and treatment with XAV939 limited SMF- and H19-mediated osteogenic differentiation of hPDLSCs. Notably, the expression of hsa-miR-532-3p, hsa-miR-370-3p, hsa-miR-18a-5p, and hsa-miR-483-3p in hPDLSCs was regulated by SMF, and may form an endogenous competitive RNA mechanism with H19 and β-catenin. CONCLUSION SMF contributes to the osteogenic differentiation of hPDLSCs by mediating the H19/Wnt/β-catenin pathway, and hsa-miR-532-3p, hsa-miR-370-3p, hsa-miR-18a-5p, and hsa-miR-483-3p may be the key factors in it.
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Affiliation(s)
- Yanling Yang
- Department of Orthodontics, Kunming Medical University School and Hospital of Stomatology, No.1088 Haiyuan Middle Road, Kunming, Yunnan 650106, China; Yunnan Key Laboratory of Stomatology, Kunming Medical University, 1168 Chunrong West Road, Kunming, Yunnan 650500, China; Center of Stomatology, Affiliated Hospital of Yunnan University, No.176 Qingnian Road, Kunming, Yunnan 650021, China
| | - Na Gao
- Laboratory of Vaccine Development, Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, No.935 Jiaoling Road Kunming, Yunnan 650118, China
| | - Guang Ji
- Laboratory of Vaccine Development, Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, No.935 Jiaoling Road Kunming, Yunnan 650118, China
| | - Wenzhu Hu
- Laboratory of Vaccine Development, Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, No.935 Jiaoling Road Kunming, Yunnan 650118, China
| | - Rong Bi
- Genetic Engineering and Vaccine Research Center, Institute of Medical Biology, Chinese Academy of Medical Science, Peking Union Medical College, No.935 Jiaoling Road Kunming, Yunnan 650118, China
| | - Jiangli Liang
- Laboratory of Vaccine Development, Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, No.935 Jiaoling Road Kunming, Yunnan 650118, China
| | - Yali Liu
- Department of Orthodontics, Kunming Medical University School and Hospital of Stomatology, No.1088 Haiyuan Middle Road, Kunming, Yunnan 650106, China; Yunnan Key Laboratory of Stomatology, Kunming Medical University, 1168 Chunrong West Road, Kunming, Yunnan 650500, China.
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Xu X, Feng J, Lin T, Liu R, Chen Z. miR-181a/MSC-Loaded Nano-Hydroxyapatite/Collagen Accelerated Bone Defect Repair in Rats by Targeting Ferroptosis Pathway. J Funct Biomater 2024; 15:385. [PMID: 39728185 DOI: 10.3390/jfb15120385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 11/20/2024] [Accepted: 12/09/2024] [Indexed: 12/28/2024] Open
Abstract
Background: The reparative regeneration of jawbone defects poses a significant challenge within the field of dentistry. Despite being the gold standard, autogenous bone materials are not without drawbacks, including a heightened risk of postoperative infections. Consequently, the development of innovative materials that can surpass the osteogenic capabilities of autologous bone has emerged as a pivotal area of research. Methods: Mesenchymal stem cells (MSCs), known for their multilineage differentiation potential, were isolated from human umbilical cords and transfected with miR-181a. The osteogenic differentiation of miR-181a/MSC was investigated. Then, physicochemical properties of miR-181a/MSC-loaded nano-hydroxyapatite (nHAC) scaffolds were characterized, and their efficacy and underlying mechanism in rat calvarial defect repair were explored. Results: miR-181a overexpression in MSCs significantly promoted osteogenic differentiation, as evidenced by increased alkaline phosphatase activity and expression of osteogenic markers. The miR-181a/MSC-loaded nHAC scaffolds exhibited favorable bioactivity and accelerated bone tissue repair and collagen secretion in vivo. Mechanistic studies reveal that miR-181a directly targeted the TP53/SLC7A11 pathway, inhibiting ferroptosis and enhancing the osteogenic capacity of MSCs. Conclusions: The study demonstrates that miR-181a/MSC-loaded nHAC scaffolds significantly enhance the repair of bone defects by promoting osteogenic differentiation and inhibiting ferroptosis. These findings provide novel insights into the molecular mechanisms regulating MSC osteogenesis and offer a promising therapeutic strategy for bone defect repair.
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Affiliation(s)
- Xiongjun Xu
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
- The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Junming Feng
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
| | - Tianze Lin
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
| | - Runheng Liu
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
| | - Zhuofan Chen
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
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Song Y, Guo N, Zi F, Zheng J, Cheng J. lncRNA H19 plays a role in multiple myeloma via interacting with hnRNPA2B1 to stabilize BET proteins by targeting osteoclasts and osteoblasts. Int Immunopharmacol 2024; 142:113080. [PMID: 39288624 DOI: 10.1016/j.intimp.2024.113080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/30/2024] [Accepted: 09/01/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND Multiple myeloma (MM), characterized with bone marrow microenvironment disorder, accounts for about 20% of hematological cancer deaths globally. Tissue extracellular communication, especially extracellular vesicles, has been defined as important mediator among cell-to-cell cross-talk. Our previous study revealed an elevated level of H19 in MM, whereas, its role in MM exosomes in the development of osteolysis remains largely unknown. METHOD MM exosomes referring to 5TGM1 cells were isolated and characterized using transmission electron microscopy (TEM), nanoparticle tracking and western blot analysis. The biological effects of blocking H19 were examined on osteolysis in vivo of C57Bl6/KalwRij mice, as well as on the osteoclast differentiation in vitro of RAW264.7 cells, by the application of TRAP, either with osteogenic differentiation in vitro of bone marrow mesenchymal stem cells (BMSCs), by the detection of alkaline phosphatase (ALP), alizarin red dye staining (ARS). The targeted relationships among H19/hnRNPA2B1/BET proteins were validated through RNA immunoprecipitation (RIP) and RNA pull-down assays. RESULTS 5TGM1 cells derived-exosomes lacking H19 dramatically blocked osteolysis and boosted osteogeneis in C57Bl6/KalwRij mice, either with osteoclastic differentiation of RAW264.7 cells and osteogenic differentiation of BMSCs, thereby enhancing their resorptive activity. Physically, H19 interacted with hnRNPA2B1 by preferentially adhering to it and enhancing its nuclear-cytoplasmic translocation. Further mechanistic research validated that H19 promoted the stabilization of BET proteins through hnRNA2B1 to be involved in osteoclast differentiation for contributing to MM progression. CONCLUSION Altogether, our findings suggest that H19, serving as an essential role for exosomes in the bone marrow environment, might be a viable diagnostic and therapeutic target for MM therapy.
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Affiliation(s)
- Yuan Song
- Department of Hematology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, PR China
| | - Ninghong Guo
- Department of Hematology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, PR China
| | - Fuming Zi
- Department of Hematology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, PR China
| | - Jifu Zheng
- Department of Hematology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, PR China
| | - Jing Cheng
- Department of Hematology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, PR China.
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Singh M, Singh P, Singh B, Sharma K, Kumar N, Singh D, Mastana S. Molecular Signaling Pathways and MicroRNAs in Bone Remodeling: A Narrative Review. Diseases 2024; 12:252. [PMID: 39452495 PMCID: PMC11507001 DOI: 10.3390/diseases12100252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 10/02/2024] [Accepted: 10/06/2024] [Indexed: 10/26/2024] Open
Abstract
Bone remodeling is an intricate process executed throughout one's whole life via the cross-talk of several cellular events, progenitor cells and signaling pathways. It is an imperative mechanism for regaining bone loss, recovering damaged tissue and repairing fractures. To achieve this, molecular signaling pathways play a central role in regulating pathological and causal mechanisms in different diseases. Similarly, microRNAs (miRNAs) have shown promising results in disease management by mediating mRNA targeted gene expression and post-transcriptional gene function. However, the role and relevance of these miRNAs in signaling processes, which regulate the delicate balance between bone formation and bone resorption, are unclear. This review aims to summarize current knowledge of bone remodeling from two perspectives: firstly, we outline the modus operandi of five major molecular signaling pathways, i.e.,the receptor activator of nuclear factor kappa-B (RANK)-osteoprotegrin (OPG) and RANK ligand (RANK-OPG-RANKL), macrophage colony-stimulating factor (M-CSF), Wnt/β-catenin, Jagged/Notch and bone morphogenetic protein (BMP) pathways in regards to bone cell formation and function; and secondly, the miRNAs that participate in these pathways are introduced. Probing the miRNA-mediated regulation of these pathways may help in preparing the foundation for developing targeted strategies in bone remodeling, repair and regeneration.
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Affiliation(s)
- Monica Singh
- Department of Human Genetics, Punjabi University, Patiala 147002, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Puneetpal Singh
- Department of Human Genetics, Punjabi University, Patiala 147002, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Baani Singh
- Department of Human Genetics, Punjabi University, Patiala 147002, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Kirti Sharma
- Department of Human Genetics, Punjabi University, Patiala 147002, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Nitin Kumar
- Department of Human Genetics, Punjabi University, Patiala 147002, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Deepinder Singh
- VardhmanMahavir Health Care, Urban Estate Ph-II, Patiala 147002, India;
| | - Sarabjit Mastana
- Human Genomics Laboratory, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough LE11 3TU, UK;
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Jiang C, Wang P, Tan Z, Zhang Y. Long non-coding RNAs in bone formation: Key regulators and therapeutic prospects. Open Life Sci 2024; 19:20220908. [PMID: 39156986 PMCID: PMC11330173 DOI: 10.1515/biol-2022-0908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/23/2024] [Accepted: 06/03/2024] [Indexed: 08/20/2024] Open
Abstract
Recent scientific investigations have revealed the intricate mechanisms underlying bone formation, emphasizing the essential role of long non-coding RNAs (lncRNAs) as critical regulators. This process, essential for skeletal strength and functionality, involves the transformation of mesenchymal stem cells into osteoblasts and subsequent deposition of bone matrix. lncRNAs, including HOX transcript antisense RNA (HOTAIR), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), differentiation antagonizing non-coding RNA (DANCR), and maternally expressed gene 3 (MEG3), have emerged as prominent players in this regulatory network. HOTAIR modulates osteoblast differentiation by interacting with chromatin-modifying enzymes, while MALAT1 regulates osteogenic differentiation through microRNA interactions. DANCR collaborates with Runx2 to fine-tune osteoblast differentiation, and MEG3 orchestrates multiple signaling pathways crucial for bone formation. Moreover, other lncRNAs such as H19, lncRNA for enhancing osteogenesis 3, rhabdomyosarcoma 2-associated transcript, urothelial cancer associated 1, taurine up-regulated gene 1, and nuclear enriched abundant transcript 1 contribute to the complex regulatory network governing osteoblast activities. Understanding the precise roles of these lncRNAs offers promising avenues for developing innovative therapeutic strategies targeting bone-related disorders like osteoporosis. Overall, this review summarizes the pivotal role of lncRNAs in bone formation, highlighting their potential as targets for future research endeavors aimed at advancing therapeutic interventions in bone diseases.
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Affiliation(s)
- Chun Jiang
- Department of Orthopedics, The People’s Hospital of SND, Suzhou, Jiangsu, 215129, China
| | - Peng Wang
- Department of Spine Surgery, Shengli Oilfield Central Hospital, Dongying, Shandong, 257000, China
| | - ZhenWei Tan
- Department of Orthopedics, Sichuan Fifth People’s Hospital, Chengdu, Sichuan, 610015, China
| | - Yin Zhang
- Department of Orthopedics, The People’s Hospital of SND, Suzhou, Jiangsu, 215129, China
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Zhu Q, Sun J, An C, Li X, Xu S, He Y, Zhang X, Liu L, Hu K, Liang M. Mechanism of LncRNA Gm2044 in germ cell development. Front Cell Dev Biol 2024; 12:1410914. [PMID: 39027044 PMCID: PMC11255455 DOI: 10.3389/fcell.2024.1410914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 06/03/2024] [Indexed: 07/20/2024] Open
Abstract
Germ cell development in mammals is a complex physiological process that involves the proliferation of primordial germ cells, meiosis, and the formation of male and female gametes. Long non-coding RNA (lncRNA) is a type of RNA with more than 200 nucleotides that does not code for proteins. A small number of lncRNAs have been shown to participate in spermatogenesis in the testes and in follicular development in the ovaries, but the role of the vast majority of lncRNAs and their molecular mechanisms still need further study. LncRNA Gm2044 was identified as a differentially expressed lncRNA in mouse spermatogenesis by microarray technology. In mouse testis, lncRNA Gm2044 can act as competing endogenous RNA to regulate SYCP1 expression in GC-2 cells derived from mouse spermatocyte cells, and it can also act as a host gene for miR-202 to regulate RBFOX2 protein expression. In female mouse ovaries, lncRNA Gm2044 regulates 17β-estradiol synthesis through the miRNA-138-5p-Nr5a1 pathway or by interacting with EEF2. In addition, studies suggest that lncRNA Gm2044 is also involved in the progression of reproductive system diseases such as male nonobstructive azoospermia. Here, we summarize the roles and molecular mechanisms of lncRNA Gm2044 in male and female gametogenesis and its potential role in some infertility disorders.
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Affiliation(s)
- Qinran Zhu
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Junpei Sun
- First Affiliated Hospital, Bengbu Medical University, Bengbu, China
| | - Chuangchuang An
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Xin Li
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Shumin Xu
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Yutong He
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Xinyi Zhang
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Lei Liu
- First Affiliated Hospital, Bengbu Medical University, Bengbu, China
| | - Ke Hu
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Meng Liang
- School of Life Science, Bengbu Medical University, Bengbu, China
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Lung H, Wentworth KL, Moody T, Zamarioli A, Ram A, Ganesh G, Kang M, Ho S, Hsiao EC. Wnt pathway inhibition with the porcupine inhibitor LGK974 decreases trabecular bone but not fibrosis in a murine model with fibrotic bone. JBMR Plus 2024; 8:ziae011. [PMID: 38577521 PMCID: PMC10994528 DOI: 10.1093/jbmrpl/ziae011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/22/2023] [Accepted: 01/08/2024] [Indexed: 04/06/2024] Open
Abstract
G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including the development, remodeling, and repair of the skeleton. Fibrous dysplasia (FD) of the bone is characterized by fibrotic, expansile bone lesions caused by activating mutations in GNAS. There are no effective therapies for FD. We previously showed that ColI(2.3)+/Rs1+ mice, in which Gs-GPCR signaling was hyper-activated in osteoblastic cell lineages using an engineered receptor strategy, developed a fibrotic bone phenotype with trabecularization that could be reversed by normalizing Gs-GPCR signaling, suggesting that targeting the Gs-GPCR or components of the downstream signaling pathway could serve as a promising therapeutic strategy for FD. The Wnt signaling pathway has been implicated in the pathogenesis of FD-like bone, but the specific Wnts and which cells produce them remain largely unknown. Single-cell RNA sequencing on long-bone stromal cells of 9-wk-old male ColI(2.3)+/Rs1+ mice and littermate controls showed that fibroblastic stromal cells in ColI(2.3)+/Rs1+ mice were expanded. Multiple Wnt ligands were up- or downregulated in different cellular populations, including in non-osteoblastic cells. Treatment with the porcupine inhibitor LGK974, which blocks Wnt signaling broadly, induced partial resorption of the trabecular bone in the femurs of ColI(2.3)+/Rs1+ mice, but no significant changes in the craniofacial skeleton. Bone fibrosis remained evident after treatment. Notably, LGK974 caused significant bone loss in control mice. These results provide new insights into the role of Wnt and Gs-signaling in fibrosis and bone formation in a mouse model of Gs-GPCR pathway overactivation.
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Affiliation(s)
- Hsuan Lung
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
- Oral and Craniofacial Sciences Graduate Program, School of Dentistry, University of California, San Francisco, CA 94143, United States
- Department of Dentistry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- School of Dentistry, Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Kelly L Wentworth
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, Zuckerberg San Francisco General Hospital, San Francisco, CA 94143, United States
| | - Tania Moody
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
| | - Ariane Zamarioli
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
- Department of Orthopaedics and Anesthesiology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo (SP) 14049-900, Brazil
| | - Apsara Ram
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
| | - Gauri Ganesh
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
| | - Misun Kang
- Oral and Craniofacial Sciences Graduate Program, School of Dentistry, University of California, San Francisco, CA 94143, United States
| | - Sunita Ho
- Oral and Craniofacial Sciences Graduate Program, School of Dentistry, University of California, San Francisco, CA 94143, United States
| | - Edward C Hsiao
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
- Oral and Craniofacial Sciences Graduate Program, School of Dentistry, University of California, San Francisco, CA 94143, United States
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Huang R, Nie W, Mi L, Yao C, Zhu H. EIF3B stabilizes PCNA by counteracting SYVN1-mediated ubiquitination to serve as a promotor in cholangiocarcinoma. Aging (Albany NY) 2024; 16:7311-7330. [PMID: 38687509 PMCID: PMC11087095 DOI: 10.18632/aging.205759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 03/05/2024] [Indexed: 05/02/2024]
Abstract
Cholangiocarcinoma, a prevalent hepatic malignancy, exhibits a progressively rising incidence. While Eukaryotic translation initiation factor 3 subunit B (EIF3B) has been implicated in the occurrence and development of various cancers, its specific roles in cholangiocarcinoma remain unexplored. Immunohistochemical (IHC) analysis was employed to detect EIF3B/PCNA expression in cholangiocarcinoma. Cells were manipulated using short hairpin RNA (shRNA)-mediated lentiviruses or overexpression plasmids. Statistical significance was assessed using the Student's t-test and one-way ANOVA, with P < 0.05 considered statistically significant. EIF3B exhibited robust expression in cholangiocarcinoma, demonstrating a significant correlation with the pathological grade of cholangiocarcinoma patients. Furthermore, modulation of EIF3B expression, either depletion or elevation, demonstrated the ability to inhibit or enhance cholangiocarcinoma cell survival and migration in vitro. Mechanistically, we identified Proliferating Cell Nuclear Antigen (PCNA) as a downstream gene of EIF3B, driving cholangiocarcinoma. EIF3B stabilized PCNA by inhibiting PCNA ubiquitination, a process mediated by E3 ligase SYVN1. Similar to EIF3B, PCNA levels were also abundant in cholangiocarcinoma, and knocking down PCNA impeded cholangiocarcinoma development. Intriguingly, silencing PCNA attenuated the promotion induced by EIF3B overexpression. Furthermore, the elevated P21 protein level in shEIF3B RBE cells was partially attenuated after UC2288 (P21 signaling pathway inhibitor) treatment. Our findings underscored the potential of EIF3B as a therapeutic target for cholangiocarcinoma. Unraveling its functions holds promise for the development of more specific and effective targeted therapy strategies.
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Affiliation(s)
- Ranglang Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of the Central South University, Changsha 400013, Hunan, P.R. China
| | - Wanpin Nie
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of the Central South University, Changsha 400013, Hunan, P.R. China
| | - Liangliang Mi
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of the Central South University, Changsha 400013, Hunan, P.R. China
| | - Chenjiao Yao
- Department of General Medicine, Third Xiangya Hospital, Central South University, Changsha 400013, Hunan, P.R. China
| | - Haixia Zhu
- Department of General Medicine, Third Xiangya Hospital, Central South University, Changsha 400013, Hunan, P.R. China
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Lu J, Xu L, Wang Y, Guan B. lncRNAs regulate cell stemness in physiology and pathology during differentiation and development. AMERICAN JOURNAL OF STEM CELLS 2024; 13:59-74. [PMID: 38765805 PMCID: PMC11101988 DOI: 10.62347/vhvu7361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 03/06/2024] [Indexed: 05/22/2024]
Abstract
Long non-coding RNA (lncRNA) are an important class of ubiquitous genes involved in diverse biological functions. lncRNAs, defined as noncoding RNAs with a length exceeding 200 nucleotides, are abundantly expressed throughout cells; however, their precise functions remain largely elusive. From embryonic stem cell proliferation and differentiation to cancer cell proliferation and invasion, lncRNAs play multifaceted regulatory roles across various cellular stages. Moreover, lncRNAs participate in the regulation of differentiation and regeneration during cellular development processes while also playing a pivotal role in maintaining and regulating cell stemness. In this article, we comprehensively review the current knowledge regarding lncRNAs in this field, discussing their biological functions and mechanisms underlying stemness regulation along with the factors implicated in these processes. We emphasize the growing evidence supporting the significance of lncRNAs in governing cell stemness while indicating that disruptions or mutations within them may serve as fundamental causes for certain developmental disorders.
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Affiliation(s)
- Jie Lu
- Department of Otolaryngology Head and Neck Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University Yangzhou, Jiangsu, China
| | - Li Xu
- Department of Otolaryngology Head and Neck Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University Yangzhou, Jiangsu, China
| | - Ying Wang
- Department of Otolaryngology Head and Neck Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University Yangzhou, Jiangsu, China
| | - Bing Guan
- Department of Otolaryngology Head and Neck Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University Yangzhou, Jiangsu, China
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Zhang Q, Li J, Wang C, Li Z, Luo P, Gao F, Sun W. N6-Methyladenosine in Cell-Fate Determination of BMSCs: From Mechanism to Applications. RESEARCH (WASHINGTON, D.C.) 2024; 7:0340. [PMID: 38665846 PMCID: PMC11045264 DOI: 10.34133/research.0340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 02/21/2024] [Indexed: 04/28/2024]
Abstract
The methylation of adenosine base at the nitrogen-6 position is referred to as "N6-methyladenosine (m6A)" and is one of the most prevalent epigenetic modifications in eukaryotic mRNA and noncoding RNA (ncRNA). Various m6A complex components known as "writers," "erasers," and "readers" are involved in the function of m6A. Numerous studies have demonstrated that m6A plays a crucial role in facilitating communication between different cell types, hence influencing the progression of diverse physiological and pathological phenomena. In recent years, a multitude of functions and molecular pathways linked to m6A have been identified in the osteogenic, adipogenic, and chondrogenic differentiation of bone mesenchymal stem cells (BMSCs). Nevertheless, a comprehensive summary of these findings has yet to be provided. In this review, we primarily examined the m6A alteration of transcripts associated with transcription factors (TFs), as well as other crucial genes and pathways that are involved in the differentiation of BMSCs. Meanwhile, the mutual interactive network between m6A modification, miRNAs, and lncRNAs was intensively elucidated. In the last section, given the beneficial effect of m6A modification in osteogenesis and chondrogenesis of BMSCs, we expounded upon the potential utility of m6A-related therapeutic interventions in the identification and management of human musculoskeletal disorders manifesting bone and cartilage destruction, such as osteoporosis, osteomyelitis, osteoarthritis, and bone defect.
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Affiliation(s)
- Qingyu Zhang
- Department of Orthopedics,
Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan 250021, China
| | - Junyou Li
- School of Mechanical Engineering,
Sungkyunkwan University, Suwon 16419, South Korea
| | - Cheng Wang
- Department of Orthopaedic Surgery,
Peking UniversityThird Hospital, Peking University, Beijing 100191, China
| | - Zhizhuo Li
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital,
the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Pan Luo
- Department of Joint Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, China
| | - Fuqiang Gao
- Department of Orthopedics, China-Japan Friendship Hospital, Beijing 100029, China
| | - Wei Sun
- Department of Orthopedics, China-Japan Friendship Hospital, Beijing 100029, China
- Department of Orthopaedic Surgery of the Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA 19104, USA
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12
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Zhou XC, Wang DX, Zhang CY, Yang YJ, Zhao RB, Liu SY, Ni GX. Exercise promotes osteogenic differentiation by activating the long non-coding RNA H19/microRNA-149 axis. World J Orthop 2024; 15:363-378. [PMID: 38680671 PMCID: PMC11045468 DOI: 10.5312/wjo.v15.i4.363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/04/2024] [Accepted: 03/19/2024] [Indexed: 04/16/2024] Open
Abstract
BACKGROUND Regular physical activity during childhood and adolescence is beneficial to bone development, as evidenced by the ability to increase bone density and peak bone mass by promoting bone formation. AIM To investigate the effects of exercise on bone formation in growing mice and to investigate the underlying mechanisms. METHODS 20 growing mice were randomly divided into two groups: Con group (control group, n = 10) and Ex group (treadmill exercise group, n = 10). Hematoxylin-eosin staining, immunohistochemistry, and micro-CT scanning were used to assess the bone formation-related indexes of the mouse femur. Bioinformatics analysis was used to find potential miRNAs targets of long non-coding RNA H19 (lncRNA H19). RT-qPCR and Western Blot were used to confirm potential miRNA target genes of lncRNA H19 and the role of lncRNA H19 in promoting osteogenic differentiation. RESULTS Compared with the Con group, the expression of bone morphogenetic protein 2 was also significantly increased. The micro-CT results showed that 8 wk moderate-intensity treadmill exercise significantly increased bone mineral density, bone volume fraction, and the number of trabeculae, and decreased trabecular segregation in the femur of mice. Inhibition of lncRNA H19 significantly upregulated the expression of miR-149 and suppressed the expression of markers of osteogenic differentiation. In addition, knockdown of lncRNA H19 significantly downregulated the expression of autophagy markers, which is consistent with the results of autophagy-related protein changes detected in mouse femurs by immunofluorescence. CONCLUSION Appropriate treadmill exercise can effectively stimulate bone formation and promote the increase of bone density and bone volume in growing mice, thus enhancing the peak bone mass of mice. The lncRNA H19/miR-149 axis plays an important regulatory role in osteogenic differentiation.
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Affiliation(s)
- Xu-Chang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Dong-Xue Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Chun-Yu Zhang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Ya-Jing Yang
- Department of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Ruo-Bing Zhao
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Sheng-Yao Liu
- Department of Spinal Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Guo-Xin Ni
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
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13
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Mai YX, Li ZP, Pang FX, Zhou ST, Li N, Wang YY, Zhang JF. Aucubin Promotes Osteogenic Differentiation and Facilitates Bone Formation through the lncRNA-H19 Driven Wnt/ β-Catenin Signaling Regulatory Axis. Stem Cells Int 2024; 2024:5388064. [PMID: 38633381 PMCID: PMC11022505 DOI: 10.1155/2024/5388064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 03/01/2024] [Accepted: 03/14/2024] [Indexed: 04/19/2024] Open
Abstract
Objectives Traditional Chinese medicine Cortex Eucommiae has been used to treat bone fracture for hundreds of years, which exerts a significant improvement in fracture healing. Aucubin, a derivative isolated from Cortex Eucommiae, has been demonstrated to possess anti-inflammatory, immunoregulatory, and antioxidative potential. In the present study, our aim was to explore its function in bone regeneration and elucidate the underlying mechanism. Materials and Methods The effects of Aucubin on osteoblast and osteoclast were examined in mouse bone marrow-derived mesenchymal stem cells (BM-MSCs) and RAW 264.7 cells, respectively. Moreover, the lncRNA H19 and Wnt/β-catenin signaling were detected by qPCR examination, western blotting, and luciferase activity assays. Using the femur fracture mice model, the in vivo effect of Aucubin on bone formation was monitored by X-ray, micro-CT, histomorphometry, and immunohistochemistry staining. Results In the present study, Aucubin was found to significantly promote osteogenic differentiation in vitro and stimulated bone formation in vivo. Regarding to the underlying mechanism, H19 was found to be obviously upregulated by Aucubin in MSCs and thus induced the activation of Wnt/β-catenin signaling. Moreover, H19 knockdown partially reversed the Aucubin-induced osteogenic differentiation and successfully suppressed the activation of Wnt/β-catenin signaling. We therefore suggested that Aucubin induced the activation of Wnt/β-catenin signaling through promoting H19 expression. Conclusion Our results demonstrated that Aucubin promoted osteogenesis in vitro and facilitated fracture healing in vivo through the H19-Wnt/β-catenin regulatory axis.
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Affiliation(s)
- Yong-xin Mai
- Cancer Center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen 518000, Guangdong, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Zhi-peng Li
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Department of Rehabilitation, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Feng-xiang Pang
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
| | - Shu-ting Zhou
- Cancer Center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen 518000, Guangdong, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Nan Li
- Cancer Center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen 518000, Guangdong, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yu-yan Wang
- Cancer Center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen 518000, Guangdong, China
| | - Jin-fang Zhang
- Cancer Center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen 518000, Guangdong, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
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14
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Qi L, Pan C, Yan J, Ge W, Wang J, Liu L, Zhang L, Lin D, Shen SGF. Mesoporous bioactive glass scaffolds for the delivery of bone marrow stem cell-derived osteoinductive extracellular vesicles lncRNA promote senescent bone defect repair by targeting the miR-1843a-5p/Mob3a/YAP axis. Acta Biomater 2024; 177:486-505. [PMID: 38311197 DOI: 10.1016/j.actbio.2024.01.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 01/24/2024] [Accepted: 01/29/2024] [Indexed: 02/10/2024]
Abstract
Bone repair in elderly patients poses a huge challenge due to the age-related progressive decline in regenerative abilities attributed to the senescence of bone marrow stem cells (BMSCs). Bioactive scaffolds have been applied in bone regeneration due to their various biological functions. In this study, we aimed to fabricate functionalized bioactive scaffolds through loading osteoinductive extracellular vesicles (OI-EVs) based on mesoporous bioactive glass (MBG) scaffolds (1010 particles/scaffold) and to investigate its effects on osteogenesis and senescence of BMSCs. The results suggested that OI-EVs upregulate the proliferative and osteogenic capacities of senescent BMSCs. More importantly, The results showed that loading OI-EVs into MBG scaffolds achieved better bone regeneration. Furthermore, OI-EVs and BMSCs RNAs bioinformatics analysis indicated that OI-EVs play roles through transporting pivotal lncRNA acting as a "sponge" to compete with Mob3a for miR-1843a-5p to promote YAP dephosphorylation and nuclear translocation, ultimately resulting in elevated proliferation and osteogenic differentiation and reduced senescence-related phenotypes. Collectively, these results suggested that the OI-EVs lncRNA ceRNA regulatory networks might be the key point for senescent osteogenesis. More importantly, the study indicated the feasibility of loading OI-EVs into scaffolds and provided novel insights into biomaterial design for facilitating bone regeneration in the treatment of senescent bone defects. STATEMENT OF SIGNIFICANCE: Constructing OI-EVs/MBG delivering system and verification of its bone regeneration enhancement in senescent defect repair. Aging bone repair poses a huge challenge due to the age-related progressive degenerative decline in regenerative abilities attributed to the senescence of BMSCs. OI-EVs/MBG delivering system were expected as promising treatment for senescent bone repair, which could provide an effective strategy for bone regeneration in elderly patients. Clarification of potential OI-EVs lncRNA ceRNA regulatory mechanism in senescent bone regeneration OI-EVs play important roles through transferring lncRNA-ENSRNOG00000056625 sponging miR-1843a-5p that targeted Mob3a to activate YAP translocation into nucleus, ultimately alleviate senescence, promote proliferation and osteogenic differentiation in O-BMSCs, which provides theoretical basis for EVs-mediated therapy in future clinical works.
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Affiliation(s)
- Lei Qi
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Cancan Pan
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Jinge Yan
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Weiwen Ge
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Jing Wang
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Lu Liu
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Lei Zhang
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China.
| | - Dan Lin
- Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China.
| | - Steve G F Shen
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China.
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15
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Zhu Y, Guan X, Geng X, Du Y, Jin S, Liu J. The signaling pathways involved in non-coding RNA regulation during osteogenic differentiation of periodontal tissue-derived cells in the field of periodontitis. J Periodontal Res 2024; 59:18-31. [PMID: 37961979 DOI: 10.1111/jre.13199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 09/07/2023] [Accepted: 10/12/2023] [Indexed: 11/15/2023]
Abstract
Periodontitis is a prevalent oral disease caused by chronic inflammation of the periodontal tissues surrounding the teeth, which can lead to bone loss, tooth loosening, and even tooth loss. This inflammation has a negative impact on the osteogenic differentiation capacity of periodontal tissue-derived cells. Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins but can regulate various physiological processes. In this review, we summarized the critical signaling pathways that ncRNAs modulate in osteogenic differentiation of periodontal tissue-derived cells, such as the Wnt, BMP/Smad, NF-κB, and PI3-K/Akt/mTOR pathways. This comprehensive exploration of ncRNA-mediated modulation offers fresh and promising insights for prospective approaches in the management of periodontitis and the advancement of periodontal regeneration therapies.
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Affiliation(s)
- Yinci Zhu
- School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Xiaoyan Guan
- Department of Orthodontics, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
| | - Xiaorui Geng
- Department of Otolaryngology. Longgang E.N.T Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T Shenzhen, Shenzhen, China
| | - Yuanhang Du
- School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Suhan Jin
- Department of Orthodontics, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
| | - Jianguo Liu
- School of Stomatology, Zunyi Medical University, Zunyi, China
- Special Key Laboratory of Oral Diseases Research, Higher Education Institution, Zunyi, China
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16
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Yan Z, He Q. LINC01234 Sponging of the miR-513a-5p/AOX1 Axis is Upregulated in Osteoporosis and Regulates Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells. Mol Biotechnol 2023; 65:2108-2118. [PMID: 36964437 DOI: 10.1007/s12033-023-00712-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/28/2023] [Indexed: 03/26/2023]
Abstract
Non-coding RNAs, including long-chain non-coding RNA (lncRNA) and micro-RNA (miRNA), have been implicated in osteoporosis (OP) progression by regulating osteoblast-dependent bone metabolism. Herein, we investigated whether LINC01234, miR-513a-5p, and AOX1 regulate osteogenic differentiation and proliferation of human bone marrow mesenchymal stem cells (hMSCs). The expression of LINC01234, miR-513a-5p, and AOX1 was monitored using RT-qPCR or western blotting. Cell proliferation was assessed using a CCK8 assay. Alkaline phosphatase activity (ALP) and alizarin red dye staining were performed to determine osteogenic differentiation. Furthermore, the expression of osteoblast differentiation markers, such as ALP, BMP1 (bone morphogenetic protein 1), osteocalcin (OCN), and osteopontin (OPN), was determined by RT-qPCR. Luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to verify the interplay between miR-513a-5p and LINC01234 or AOX1. Compared with the plasma of healthy controls, LINC01234 and AOX1 were highly expressed in the plasma of patients with OP, whereas miR-513a-5p showed low expression. In contrast, LINC01234 and AOX1 expression displayed a gradual decrease in induced differentiated hMSCs, while miR-513a-5p expression was upregulated with induction time. The predicted binding sites between miR-513a-5p and LINC01234 or AOX1 were verified by luciferase reporter and RIP assays. LINC01234 silencing induced osteogenic differentiation and proliferation in vitro, and miR-513a-5p silencing blunted osteogenic differentiation and proliferation modulated by LINC01234. AOX1 silencing caused by miR-513a-5p enhances osteogenic proliferation and differentiation. LINC01234 sponging of the miR-513a-5p/AOX1 axis impeded the osteogenic differentiation of hMSCs, favoring OP progression.
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Affiliation(s)
- Zhiyuan Yan
- Out-Patient Department, Bayi Orthopedic Hospital, Chengdu, 610031, Sichuan, China
| | - Qiansong He
- Administrative Office, Bayi Orthopedic Hospital, No.3 Wudu Road, Qingyang District, Chengdu, 610031, Sichuan, China.
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17
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Khotib J, Marhaeny HD, Miatmoko A, Budiatin AS, Ardianto C, Rahmadi M, Pratama YA, Tahir M. Differentiation of osteoblasts: the links between essential transcription factors. J Biomol Struct Dyn 2023; 41:10257-10276. [PMID: 36420663 DOI: 10.1080/07391102.2022.2148749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 11/12/2022] [Indexed: 11/27/2022]
Abstract
Osteoblasts, cells derived from mesenchymal stem cells (MSCs) in the bone marrow, are cells responsible for bone formation and remodeling. The differentiation of osteoblasts from MSCs is triggered by the expression of specific genes, which are subsequently controlled by pro-osteogenic pathways. Mature osteoblasts then differentiate into osteocytes and are embedded in the bone matrix. Dysregulation of osteoblast function can cause inadequate bone formation, which leads to the development of bone disease. Various key molecules are involved in the regulation of osteoblastogenesis, which are transcription factors. Previous studies have heavily examined the role of factors that control gene expression during osteoblastogenesis, both in vitro and in vivo. However, the systematic relationship of these transcription factors remains unknown. The involvement of ncRNAs in this mechanism, particularly miRNAs, lncRNAs, and circRNAs, has been shown to influence transcriptional factor activity in the regulation of osteoblast differentiation. Here, we discuss nine essential transcription factors involved in osteoblast differentiation, including Runx2, Osx, Dlx5, β-catenin, ATF4, Ihh, Satb2, and Shn3. In addition, we summarize the role of ncRNAs and their relationship to these essential transcription factors in order to improve our understanding of the transcriptional regulation of osteoblast differentiation. Adequate exploration and understanding of the molecular mechanisms of osteoblastogenesis can be a critical strategy in the development of therapies for bone-related diseases.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Junaidi Khotib
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia
| | - Honey Dzikri Marhaeny
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia
| | - Andang Miatmoko
- Department of Pharmaceutical Science, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia
| | - Aniek Setiya Budiatin
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia
| | - Chrismawan Ardianto
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia
| | - Mahardian Rahmadi
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia
| | - Yusuf Alif Pratama
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia
| | - Muhammad Tahir
- Department of Pharmaceutical Science, Kulliyah of Pharmacy, International Islamic University Malaysia, Pahang, Malaysia
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18
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Jankowski M, Farzaneh M, Ghaedrahmati F, Shirvaliloo M, Moalemnia A, Kulus M, Ziemak H, Chwarzyński M, Dzięgiel P, Zabel M, Piotrowska-Kempisty H, Bukowska D, Antosik P, Mozdziak P, Kempisty B. Unveiling Mesenchymal Stem Cells' Regenerative Potential in Clinical Applications: Insights in miRNA and lncRNA Implications. Cells 2023; 12:2559. [PMID: 37947637 PMCID: PMC10649218 DOI: 10.3390/cells12212559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/20/2023] [Accepted: 10/28/2023] [Indexed: 11/12/2023] Open
Abstract
It is now widely recognized that mesenchymal stem cells (MSCs) possess the capacity to differentiate into a wide array of cell types. Numerous studies have identified the role of lncRNA in the regulation of MSC differentiation. It is important to elucidate the role and interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of signalling pathways that govern MSC function. Furthermore, miRNAs and lncRNAs are important clinical for innovative strategies aimed at addressing a wide spectrum of existing and emerging disease. Hence it is important to consider their impact on MSC function and differentiation. Examining the data available in public databases, we have collected the literature containing the latest discoveries pertaining to human stem cells and their potential in both fundamental research and clinical applications. Furthermore, we have compiled completed clinical studies that revolve around the application of MSCs, shedding light on the opportunities presented by harnessing the regulatory potential of miRNAs and lncRNAs. This exploration of the therapeutic possibilities offered by miRNAs and lncRNAs within MSCs unveils exciting prospects for the development of precision therapies and personalized treatment approaches. Ultimately, these advancements promise to augment the efficacy of regenerative strategies and produce positive outcomes for patients. As research in this field continues to evolve, it is imperative to explore and exploit the vast potential of miRNAs and lncRNAs as therapeutic agents. The findings provide a solid basis for ongoing investigations, fuelling the quest to fully unlock the regenerative potential of MSCs.
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Affiliation(s)
- Maurycy Jankowski
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, 60-812 Poznan, Poland;
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Farhoodeh Ghaedrahmati
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Milad Shirvaliloo
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Future Science Group, Unitec House, 2 Albert Place, London N3 1QB, UK
| | - Arash Moalemnia
- Faculty of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Hanna Ziemak
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Mikołaj Chwarzyński
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Physiotherapy, Wroclaw University School of Physical Education, 50-038 Wroclaw, Poland
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Division of Anatomy and Histology, University of Zielona Góra, 65-046 Zielona Góra, Poland
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27607, USA
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27613, USA
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27613, USA
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 602 00 Brno, Czech Republic
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19
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Quadri N, Upadhyai P. Primary cilia in skeletal development and disease. Exp Cell Res 2023; 431:113751. [PMID: 37574037 DOI: 10.1016/j.yexcr.2023.113751] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/09/2023] [Accepted: 08/11/2023] [Indexed: 08/15/2023]
Abstract
Primary cilia are non-motile, microtubule-based sensory organelle present in most vertebrate cells with a fundamental role in the modulation of organismal development, morphogenesis, and repair. Here we focus on the role of primary cilia in embryonic and postnatal skeletal development. We examine evidence supporting its involvement in physiochemical and developmental signaling that regulates proliferation, patterning, differentiation and homeostasis of osteoblasts, chondrocytes, and their progenitor cells in the skeleton. We discuss how signaling effectors in mechanotransduction and bone development, such as Hedgehog, Wnt, Fibroblast growth factor and second messenger pathways operate at least in part at the primary cilium. The relevance of primary cilia in bone formation and maintenance is underscored by a growing list of rare genetic skeletal ciliopathies. We collate these findings and summarize the current understanding of molecular factors and mechanisms governing primary ciliogenesis and ciliary function in skeletal development and disease.
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Affiliation(s)
- Neha Quadri
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Priyanka Upadhyai
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
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Arai M, Ochi H, Sunamura S, Ito N, Nangaku M, Takeda S, Sato S. A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/β-Catenin Signaling Pathway. Int J Mol Sci 2023; 24:13633. [PMID: 37686441 PMCID: PMC10488071 DOI: 10.3390/ijms241713633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 08/30/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023] Open
Abstract
The vast majority of transcribed RNAs are noncoding RNAs. Among noncoding RNAs, long noncoding RNAs (lncRNAs), which contain hundreds to thousands of bases, have received attention in many fields. The vast majority of the constituent cells in bone tissue are osteocytes, but their regulatory mechanisms are incompletely understood. Considering the wide range of potential contributions of lncRNAs to physiological processes and pathological conditions, we hypothesized that lncRNAs in osteocytes, which have not been reported, could be involved in bone metabolism. Here, we first isolated osteocytes from femurs of mice with osteocyte-specific GFP expression. Then, through RNA-sequencing, we identified osteocyte-specific lncRNAs and focused on a novel lncRNA, 9530026P05Rik (lncRNA953Rik), which strongly suppressed osteogenic differentiation. In the IDG-SW3 osteocyte line with lncRNA953Rik overexpression, the expression of Osterix and its downstream genes was reduced. RNA pull-down and subsequent LC-MS/MS analysis revealed that lncRNA953Rik bound the nuclear protein CCAR2. We demonstrated that CCAR2 promoted Wnt/β-catenin signaling and that lncRNA953Rik inhibited this pathway. lncRNA953Rik sequestered CCAR2 from HDAC1, leading to deacetylation of H3K27 in the Osterix promoter and consequent transcriptional downregulation of Osterix. This research is the first to clarify the role of a lncRNA in osteocytes. Our findings can pave the way for novel therapeutic options targeting lncRNAs in osteocytes to treat bone metabolic diseases such as osteoporosis.
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Affiliation(s)
- Makoto Arai
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Hiroki Ochi
- Department of Rehabilitation for Motor Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Tokorozawa 359-8555, Japan
| | - Satoko Sunamura
- Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo 113-8519, Japan
| | - Nobuaki Ito
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, Japan
- Osteoporosis Center, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Shu Takeda
- Division of Endocrinology, Toranomon Hospital Endocrine Center, Tokyo 105-8470, Japan
| | - Shingo Sato
- Center for Innovative Cancer Treatment, Tokyo Medical and Dental University (TMDU), Tokyo 113-8519, Japan
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21
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Stefańska K, Nemcova L, Blatkiewicz M, Żok A, Kaczmarek M, Pieńkowski W, Mozdziak P, Piotrowska-Kempisty H, Kempisty B. Expression Profile of New Marker Genes Involved in Differentiation of Human Wharton's Jelly-Derived Mesenchymal Stem Cells into Chondrocytes, Osteoblasts, Adipocytes and Neural-like Cells. Int J Mol Sci 2023; 24:12939. [PMID: 37629120 PMCID: PMC10455417 DOI: 10.3390/ijms241612939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/10/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
Wharton's jelly (WJ) contains mesenchymal stem cells (MSCs) exhibiting broad immunomodulatory properties and differentiation capacity, which makes them a promising tool for cellular therapies. Although the osteogenic, chondrogenic and adipogenic differentiation is a gold standard for proper identification of MSCs, it is important to elucidate the exact molecular mechanisms governing these processes to develop safe and efficient cellular therapies. Umbilical cords were collected from healthy, full-term deliveries, for subsequent MSCs (WJ-MSCs) isolation. WJ-MSCs were cultivated in vitro for osteogenic, chondrogenic, adipogenic and neurogenic differentiation. The RNA samples were isolated and the transcript levels were evaluated using NovaSeq platform, which led to the identification of differentially expressed genes. Expression of H19 and SLPI was enhanced in adipocytes, chondrocytes and osteoblasts, and NPPB was decreased in all analyzed groups compared to the control. KISS1 was down-regulated in adipocytes, chondrocytes, and neural-like cells compared to the control. The most of identified genes were already implicated in differentiation of MSCs; however, some genes (PROK1, OCA2) have not yet been associated with initiating final cell fate. The current results indicate that both osteo- and adipo-induced WJ-MSCs share many similarities regarding the most overexpressed genes, while the neuro-induced WJ-MSCs are quite distinctive from the other three groups. Overall, this study provides an insight into the transcriptomic changes occurring during the differentiation of WJ-MSCs and enables the identification of novel markers involved in this process, which may serve as a reference for further research exploring the role of these genes in physiology of WJ-MSCs and in regenerative medicine.
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Affiliation(s)
- Katarzyna Stefańska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Cellivia 3 S.A., 61-623 Poznan, Poland
| | - Lucie Nemcova
- Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, 27721 Libechov, Czech Republic
| | - Małgorzata Blatkiewicz
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
| | - Agnieszka Żok
- Division of Philosophy of Medicine and Bioethics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Mariusz Kaczmarek
- Department of Cancer Immunology, Poznan University of Medical Sciences, 61-866 Poznan, Poland
- Gene Therapy Laboratory, Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Wojciech Pieńkowski
- Division of Perinatology and Women’s Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 60177 Brno, Czech Republic
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27695, USA
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22
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An F, Wang X, Wang C, Liu Y, Sun B, Zhang J, Gao P, Yan C. Research progress on the role of lncRNA-miRNA networks in regulating adipogenic and osteogenic differentiation of bone marrow mesenchymal stem cells in osteoporosis. Front Endocrinol (Lausanne) 2023; 14:1210627. [PMID: 37645421 PMCID: PMC10461560 DOI: 10.3389/fendo.2023.1210627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 07/26/2023] [Indexed: 08/31/2023] Open
Abstract
Osteoporosis (OP) is characterized by a decrease in osteoblasts and an increase in adipocytes in the bone marrow compartment, alongside abnormal bone/fat differentiation, which ultimately results in imbalanced bone homeostasis. Bone marrow mesenchymal stem cells (BMSCs) can differentiate into osteoblasts and adipocytes to maintain bone homeostasis. Several studies have shown that lncRNAs are competitive endogenous RNAs that form a lncRNA-miRNA network by targeting miRNA for the regulation of bone/fat differentiation in BMSCs; this mechanism is closely related to the corresponding treatment of OP and is important in the development of novel OP-targeted therapies. However, by reviewing the current literature, it became clear that there are limited summaries discussing the effects of the lncRNA-miRNA network on osteogenic/adipogenic differentiation in BMSCs. Therefore, this article provides a review of the current literature to explore the impact of the lncRNA-miRNA network on the osteogenic/adipogenic differentiation of BMSCs, with the aim of providing a new theoretical basis for the treatment of OP.
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Affiliation(s)
- Fangyu An
- Teaching Experiment Training Center, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Xiaxia Wang
- School of Tradional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Chunmei Wang
- School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Ying Liu
- School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Bai Sun
- School of Tradional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Jie Zhang
- School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Peng Gao
- School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Chunlu Yan
- School of Tradional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
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23
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Zhang X, Yan Q, Liu X, Gao J, Xu Y, Jin Z, Qin W. LncRNA00638 promotes the osteogenic differentiation of periodontal mesenchymal stem cells from periodontitis patients under static mechanical strain. Stem Cell Res Ther 2023; 14:177. [PMID: 37434256 DOI: 10.1186/s13287-023-03404-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/14/2022] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND The osteogenic differentiation capacity of periodontal mesenchymal stem cells (PDLSCs) can be influenced by different levels of static mechanical strain (SMS) in an inflammatory microenvironment. Long non-coding RNAs (lncRNAs) are involved in various physiological processes. However, the mechanisms by which lncRNAs regulate the osteogenic differentiation of PDLSCs remain unclear. METHODS We investigated the responses of PDLSCs obtained from periodontitis patients and healthy people to 8% and 12%SMS. Gene microarray and bioinformatics analyses were implemented and identified lncRNA00638 as a target gene for the osteogenesis of PDLSCs from periodontitis patients under SMS. Competing endogenous RNA (ceRNA) network analysis was applied and predicted interactions among lncRNA00638, miRNA-424-5p, and fibroblast growth factor receptor 1 (FGFR1). Gene expression levels were regulated by lentiviral vectors. Cell Counting Kit-8 assays, alkaline phosphatase assays, and Alizarin Red S staining were used to examine the osteogenic potential. RT-qPCR and Western blot were performed to detect the expression levels of related genes and proteins. RESULTS We found that 8% and 12% SMS exerted distinct effects on HPDLSCs and PPDLSCs, with 12% SMS having the most significant effect. By microarray analysis, we detected differentially expressed lncRNAs/mRNAs between 12% SMS strained and static PPDLSCs, among which lncRNA00638 was detected as a positive target gene to promote the osteogenic differentiation of PPDLSCs under SMS loading. Mechanistically, lncRNA00638 may act as a ceRNA for miR-424-5p to compete with FGFR1. In this process, lncRNA00638 and miR-424-5p suppress each other and form a network to regulate FGFR1. CONCLUSIONS Our findings demonstrate that the lncRNA00638/miRNA-424-5p/FGFR1 regulatory network is actively involved in the regulation of PDLSC osteogenic differentiation from periodontitis patients under SMS loading, which may provide evidence for optimizing orthodontic treatments in patients with periodontitis.
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Affiliation(s)
- Xiaochen Zhang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, China
| | - Qing Yan
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, China
| | - Xulin Liu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, China
| | - Jie Gao
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, China
| | - Yuerong Xu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, China
| | - Zuolin Jin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, China.
| | - Wen Qin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, China.
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24
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Liao J, Chen B, Zhu Z, Du C, Gao S, Zhao G, Zhao P, Wang Y, Wang A, Schwartz Z, Song L, Hong J, Wagstaff W, Haydon RC, Luu HH, Fan J, Reid RR, He TC, Shi L, Hu N, Huang W. Long noncoding RNA (lncRNA) H19: An essential developmental regulator with expanding roles in cancer, stem cell differentiation, and metabolic diseases. Genes Dis 2023; 10:1351-1366. [PMID: 37397543 PMCID: PMC10311118 DOI: 10.1016/j.gendis.2023.02.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 01/07/2023] [Accepted: 02/08/2023] [Indexed: 07/04/2023] Open
Abstract
Recent advances in deep sequencing technologies have revealed that, while less than 2% of the human genome is transcribed into mRNA for protein synthesis, over 80% of the genome is transcribed, leading to the production of large amounts of noncoding RNAs (ncRNAs). It has been shown that ncRNAs, especially long non-coding RNAs (lncRNAs), may play crucial regulatory roles in gene expression. As one of the first isolated and reported lncRNAs, H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis, development, tumorigenesis, osteogenesis, and metabolism. Mechanistically, H19 mediates diverse regulatory functions by serving as competing endogenous RNAs (CeRNAs), Igf2/H19 imprinted tandem gene, modular scaffold, cooperating with H19 antisense, and acting directly with other mRNAs or lncRNAs. Here, we summarized the current understanding of H19 in embryogenesis and development, cancer development and progression, mesenchymal stem cell lineage-specific differentiation, and metabolic diseases. We discussed the potential regulatory mechanisms underlying H19's functions in those processes although more in-depth studies are warranted to delineate the exact molecular, cellular, epigenetic, and genomic regulatory mechanisms underlying the physiological and pathological roles of H19. Ultimately, these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.
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Affiliation(s)
- Junyi Liao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Bowen Chen
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Zhenglin Zhu
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Chengcheng Du
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Shengqiang Gao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Piao Zhao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Zander Schwartz
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- School of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Lily Song
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jeffrey Hong
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- The Medical Scientist Training Program, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Lewis Shi
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Ning Hu
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Wei Huang
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
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25
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Hu Z, Jiang Z, Meng S, Liu R, Yang K. Research Progress on the Osteogenesis-Related Regulatory Mechanisms of Human Umbilical Cord Mesenchymal Stem Cells. Stem Cell Rev Rep 2023; 19:1252-1267. [PMID: 36917312 DOI: 10.1007/s12015-023-10521-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2023] [Indexed: 03/16/2023]
Abstract
In recent years, research on human umbilical cord mesenchymal stem cells (hUCMSCs) derived from human umbilical cord tissue has accelerated and entered clinical application research. Compared with mesenchymal stem cells (MSCs) from other sources, hUCMSCs can be extracted from different parts of umbilical cord or from the whole umbilical cord. It has the characteristics of less ethical controversy, high differentiation potential, strong proliferation ability, efficient expansion in vitro, avoiding immune rejection and immune privilege, and avoids the limitations of lack of embryonic stem cells, heterogeneity, ethical and moral constraints. hUCMSCs avoid the need for embryonic stem cell sources, heterogeneity, and ethical and moral constraints. Bone defects are very common in clinical practice, but completely effective bone tissue regeneration treatment is challenging. Currently, autologous bone transplantation and allogeneic bone transplantation are main treatment approaches in clinical work, but each has different shortcomings, such as limited sources, invasiveness, immune rejection and insufficient osteogenic ability. Therefore, to solve the bottleneck of bone tissue regeneration and repair, a great amount of research has been carried out to explore the clinical advantages of hUCMSCs as seed cells to promote osteogenesis.However, the regulation of osteogenic differentiation of hUCMSCs is an extremely complex process. Although a large number of studies have demonstrated that the role of hUCMSCs in enhancing local bone regeneration and repair through osteogenic differentiation and transplantation into the body involves multiple signaling pathways, there is no relevant article that summarize the findings. This article discusses the osteogenesis-related regulatory mechanisms of hUCMSCs, summarizes the currently known related mechanisms, and speculates on the possible signals.
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Affiliation(s)
- Zhengqi Hu
- Department of Periodontology, Hospital of Stomatology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Zhiliang Jiang
- Department of Periodontology, Hospital of Stomatology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Shengzi Meng
- Department of Periodontology, Hospital of Stomatology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Rong Liu
- Department of Periodontology, Hospital of Stomatology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Kun Yang
- Department of Periodontology, Hospital of Stomatology, Zunyi Medical University, Zunyi, 563000, Guizhou, China.
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26
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Esawy MM, Ebaid AM, Abd-Elhameed A, Thagfan FA, Mubaraki MA, Alazzouni AS, Dkhil MA, Shabana MA. Assessment of Circulating lncRNA H19 in Ankylosing Spondylitis Patients and Its Correlation with Disease Activity. J Pers Med 2023; 13:914. [PMID: 37373903 DOI: 10.3390/jpm13060914] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disease that results in severe pain and stiffness in the joints. The causes and pathophysiology of AS are still largely unknown. The lncRNA H19 plays key roles in the pathogenesis of AS by mediating inflammatory progression by acting in the axis of IL-17A/IL-23. The aims of this study were determining the role of lncRNA H19 in AS and assessing its clinical correlation. A case-control study was conducted and qRT-PCR was utilized to measure H19 expression. Comparing AS cases to healthy controls, it was found that H19 expression was significantly upregulated. For AS prediction, H19 demonstrated a 81.1% sensitivity, 100% specificity, and 90.6% diagnostic accuracy at a lncRNA H19 expression value of 1.41. lncRNA H19 had a significantly positive correlation with AS activity, MRI results, and inflammatory markers. lncRNA H19 seemed to be an independent predictor of AS (adjusted OR of 211 (95% CI: 4.7-939; p = 0.025)). After 3 months of clinical follow-up, seventeen patients (32.1%) showed minimal clinical improvement and fifteen patients (28.3%) showed major improvement. AS activity scores were significantly decreased in patients with high H19 expression. A significantly elevated lncRNA H19 expression was observed in AS cases compared with that in healthy controls. These results suggest that upregulation of lncRNA H19 expression may be involved in the pathogenesis of AS. The expression of the lncRNA H19 is related to the duration and activity of the disease. LncRNA H19 expression seems to be an independent predictor of AS.
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Affiliation(s)
- Marwa M Esawy
- Clinical Pathology Department, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Amany M Ebaid
- Rheumatology and Rehabilitation Department, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Amir Abd-Elhameed
- Internal Medicine Department, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Felwa A Thagfan
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Murad A Mubaraki
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia
| | - Ahmed S Alazzouni
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo 11795, Egypt
| | - Mohamed A Dkhil
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo 11795, Egypt
- Applied Science Research Center, Applied Science Private University, Amman 11931, Jordan
| | - Marwa A Shabana
- Clinical Pathology Department, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt
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27
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Schwarzenbach H, Gahan PB. Interplay between LncRNAs and microRNAs in Breast Cancer. Int J Mol Sci 2023; 24:ijms24098095. [PMID: 37175800 PMCID: PMC10179369 DOI: 10.3390/ijms24098095] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
(1) Although long noncoding RNAs (lncRNAs) are known to be precursors of microRNAs (miRNAs), they frequently act as competing endogoneous RNAs (ceRNAs), yet still their interplay with miRNA is not well known. However, their interaction with miRNAs may result in the modulation of miRNA action. (2) To determine the contribution of these RNA molecules in tumor resistance to chemotherapeutic drugs, it is essential to consider not only the oncogenic and tumor suppressive function of miRNAs but also the impact of lncRNAs on miRNAs. Therefore, we performed an extensive search in different databases including PubMed. (3) The present study concerns the interplay between lncRNAs and miRNAs in the regulatory post-transcriptional network and their impact on drugs used in the treatment of breast cancer. (4) Consideration of this interplay may improve the search for new drugs to circumvent chemoresistance.
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Affiliation(s)
- Heidi Schwarzenbach
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Peter B Gahan
- Fondazione "Enrico Puccinelli" Onlus, 06126 Perugia, Italy
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28
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Mishra A, Kumar R, Mishra SN, Vijayaraghavalu S, Tiwari NK, Shukla GC, Gurusamy N, Kumar M. Differential Expression of Non-Coding RNAs in Stem Cell Development and Therapeutics of Bone Disorders. Cells 2023; 12:cells12081159. [PMID: 37190068 PMCID: PMC10137108 DOI: 10.3390/cells12081159] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/26/2023] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
Stem cells' self-renewal and multi-lineage differentiation are regulated by a complex network consisting of signaling factors, chromatin regulators, transcription factors, and non-coding RNAs (ncRNAs). Diverse role of ncRNAs in stem cell development and maintenance of bone homeostasis have been discovered recently. The ncRNAs, such as long non-coding RNAs, micro RNAs, circular RNAs, small interfering RNA, Piwi-interacting RNAs, etc., are not translated into proteins but act as essential epigenetic regulators in stem cells' self-renewal and differentiation. Different signaling pathways are monitored efficiently by the differential expression of ncRNAs, which function as regulatory elements in determining the fate of stem cells. In addition, several species of ncRNAs could serve as potential molecular biomarkers in early diagnosis of bone diseases, including osteoporosis, osteoarthritis, and bone cancers, ultimately leading to the development of new therapeutic strategies. This review aims to explore the specific roles of ncRNAs and their effective molecular mechanisms in the growth and development of stem cells, and in the regulation of osteoblast and osteoclast activities. Furthermore, we focus on and explore the association of altered ncRNA expression with stem cells and bone turnover.
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Affiliation(s)
- Anurag Mishra
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, India
| | - Rishabh Kumar
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, India
| | - Satya Narayan Mishra
- Maa Gayatri College of Pharmacy, Dr. APJ Abdul Kalam Technical University, Prayagraj 211009, India
| | | | - Neeraj Kumar Tiwari
- Department of IT-Satellite Centre, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, India
| | - Girish C Shukla
- Department of Biological, Geological, and Environmental Sciences, 2121 Euclid Ave., Cleveland, OH 44115, USA
- Center for Gene Regulation in Health and Disease, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Narasimman Gurusamy
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Munish Kumar
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, India
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Feng L, Yang Z, Hou N, Wang M, Lu X, Li Y, Wang H, Wang Y, Bai S, Zhang X, Lin Y, Yan X, Lin S, Tortorella MD, Li G. Long Non-Coding RNA Malat1 Increases the Rescuing Effect of Quercetin on TNFα-Impaired Bone Marrow Stem Cell Osteogenesis and Ovariectomy-Induced Osteoporosis. Int J Mol Sci 2023; 24:5965. [PMID: 36983039 PMCID: PMC10059267 DOI: 10.3390/ijms24065965] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/09/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Osteoporosis, a common systematic bone homeostasis disorder related disease, still urgently needs innovative treatment methods. Several natural small molecules were found to be effective therapeutics in osteoporosis. In the present study, quercetin was screened out from a library of natural small molecular compounds by a dual luciferase reporter system. Quercetin was found to upregulate Wnt/β-catenin while inhibiting NF-κB signaling activities, and thereby rescuing osteoporosis-induced tumor necrosis factor alpha (TNFα) impaired BMSCs osteogenesis. Furthermore, a putative functional lncRNA, Malat1, was shown to be a key mediator in quercetin regulated signaling activities and TNFα-impaired BMSCs osteogenesis, as mentioned above. In an ovariectomy (OVX)-induced osteoporosis mouse model, quercetin administration could significantly rescue OVX-induced bone loss and structure deterioration. Serum levels of Malat1 were also obviously rescued in the OVX model after quercetin treatment. In conclusion, our study demonstrated that quercetin could rescue TNFα-impaired BMSCs osteogenesis in vitro and osteoporosis-induced bone loss in vivo, in a Malat1-dependent manner, suggesting that quercetin may serve as a therapeutic candidate for osteoporosis treatment.
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Affiliation(s)
- Lu Feng
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Zhengmeng Yang
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Nan Hou
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Ming Wang
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Xuan Lu
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Yucong Li
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Haixing Wang
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Yaofeng Wang
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
| | - Shanshan Bai
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Xiaoting Zhang
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Yuejun Lin
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Xu Yan
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Sien Lin
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Micky D. Tortorella
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
| | - Gang Li
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen 518000, China
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Moura SR, Freitas J, Ribeiro-Machado C, Lopes J, Neves N, Canhão H, Rodrigues AM, Barbosa MA, Almeida MI. Long non-coding RNA H19 regulates matrisome signature and impacts cell behavior on MSC-engineered extracellular matrices. Stem Cell Res Ther 2023; 14:37. [PMID: 36882843 PMCID: PMC9993741 DOI: 10.1186/s13287-023-03250-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 12/25/2022] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND The vast and promising class of long non-coding RNAs (lncRNAs) has been under investigation for distinct therapeutic applications. Nevertheless, their role as molecular drivers of bone regeneration remains poorly studied. The lncRNA H19 mediates osteogenic differentiation of Mesenchymal Stem/Stromal Cells (MSCs) through the control of intracellular pathways. However, the effect of H19 on the extracellular matrix (ECM) components is still largely unknown. This research study was designed to decode the H19-mediated ECM regulatory network, and to reveal how the decellularized siH19-engineered matrices influence MSC proliferation and fate. This is particularly relevant for diseases in which the ECM regulation and remodeling processes are disrupted, such as osteoporosis. METHODS Mass spectrometry-based quantitative proteomics analysis was used to identify ECM components, after oligonucleotides delivery to osteoporosis-derived hMSCs. Moreover, qRT-PCR, immunofluorescence and proliferation, differentiation and apoptosis assays were performed. Engineered matrices were decellularized, characterized by atomic force microscopy and repopulated with hMSC and pre-adipocytes. Clinical bone samples were characterized by histomorphometry analysis. RESULTS Our study provides an in-depth proteome-wide and matrisome-specific analysis of the ECM proteins controlled by the lncRNA H19. Using bone marrow-isolated MSC from patients with osteoporosis, we identified fibrillin-1 (FBN1), vitronectin (VTN) and collagen triple helix repeat containing 1 (CTHRC1), among others, as having different pattern levels following H19 silencing. Decellularized siH19-engineered matrices are less dense and have a decreased collagen content compared with control matrices. Repopulation with naïve MSCs promotes a shift towards the adipogenic lineage in detriment of the osteogenic lineage and inhibits proliferation. In pre-adipocytes, these siH19-matrices enhance lipid droplets formation. Mechanistically, H19 is targeted by miR-29c, whose expression is decreased in osteoporotic bone clinical samples. Accordingly, miR-29c impacts MSC proliferation and collagen production, but does not influence ALP staining or mineralization, revealing that H19 silencing and miR-29c mimics have complementary but not overlapping functions. CONCLUSION Our data suggest H19 as a therapeutic target to engineer the bone ECM and to control cell behavior.
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Affiliation(s)
- Sara Reis Moura
- Instituto de Investigação E Inovação Em Saúde (i3S), Universidade Do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade Do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade Do Porto, Porto, Portugal
| | - Jaime Freitas
- Instituto de Investigação E Inovação Em Saúde (i3S), Universidade Do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade Do Porto, Porto, Portugal
| | - Cláudia Ribeiro-Machado
- Instituto de Investigação E Inovação Em Saúde (i3S), Universidade Do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade Do Porto, Porto, Portugal
| | - Jorge Lopes
- Departamento de Ortopedia, Centro Hospitalar Universitário São João (CHUSJ), Porto, Portugal
| | - Nuno Neves
- Instituto de Investigação E Inovação Em Saúde (i3S), Universidade Do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade Do Porto, Porto, Portugal.,Departamento de Ortopedia, Centro Hospitalar Universitário São João (CHUSJ), Porto, Portugal.,Hospital CUF, Porto, Portugal.,Faculdade de Medicina (FMUP), Universidade Do Porto, Porto, Portugal
| | - Helena Canhão
- NOVA Medical School - Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.,Comprehensive Health Research Center (CHRC), Universidade Nova de Lisboa, Lisbon, Portugal
| | - Ana Maria Rodrigues
- NOVA Medical School - Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.,Comprehensive Health Research Center (CHRC), Universidade Nova de Lisboa, Lisbon, Portugal
| | - Mário Adolfo Barbosa
- Instituto de Investigação E Inovação Em Saúde (i3S), Universidade Do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade Do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade Do Porto, Porto, Portugal
| | - Maria Inês Almeida
- Instituto de Investigação E Inovação Em Saúde (i3S), Universidade Do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal. .,Instituto de Engenharia Biomédica (INEB), Universidade Do Porto, Porto, Portugal. .,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade Do Porto, Porto, Portugal.
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Zhang R, Zhang X, Zhang W, Cui W, Xiao Y, Liu L, Zhi S, Feng X, Liu X, Shen Y, Chai J, Hao J. Sohlh2 Regulates the Stemness and Differentiation of Colon Cancer Stem Cells by Downregulating LncRNA-H19 Transcription. Mol Cancer Res 2023; 21:115-126. [PMID: 36287177 DOI: 10.1158/1541-7786.mcr-22-0134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 07/01/2022] [Accepted: 10/13/2022] [Indexed: 02/03/2023]
Abstract
Colon cancer stem cells (CSC) are tumor-initiating cells that drive tumorigenesis and progression through self-renewal and various differentiation potency. Therefore, the identification of factors critical for colon CSC function is vital for the development of therapies. Sohlh2 belongs to the superfamily of bhlh transcription factors and serves as a tumor suppressor in several tumors. The role of Sohlh2 in CSCs remains unknown. Here we demonstrated that Sohlh2 was related to the inhibition of LncRNA-H19/miR-141/β-catenin signaling and led to the consequent suppression of colon CSC stemness and the promotion of colon CSC differentiation in vitro and in vivo. Moreover, Sohlh2 could directly bind to the promoter of LncRNA-H19 and repress its transcription activity. LncRNA-H19 mediated the effects of Sohlh2 on colon CSC stemness and differentiation. Clinically, we observed a significant inverse correlation between Sohlh2 and LncRNA-H19, β-catenin, Lgr5, CD133 expression levels, and positive correlation between Sohlh2 and MUC2, TFF2 expression in colon cancer tissues. Collectively, our findings suggest an important role of the Sohlh2/LncRNA-H19/miR-141/β-catenin pathway in regulating colon CSC stemness and differentiation, suggesting potential therapeutic targets for colon cancer. IMPLICATIONS This study identifies that Sohlh2 directly manipulates LncRNA-H19 transcription and suppresses the β-catenin signaling pathway and the Sohlh2/LncRNA-H19/miR-141/β-catenin signaling pathway plays an essential role in the stemness of colon CSCs.
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Affiliation(s)
- Ruihong Zhang
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Xiaoli Zhang
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Wenfang Zhang
- Department of Reproductive Medicine, Linyi Maternal and Child Health Care Hospital, Shandong, China
| | - Weiwei Cui
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Yunling Xiao
- Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Lanlan Liu
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Sujuan Zhi
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Xiaoning Feng
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Xuyue Liu
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Ying Shen
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Jie Chai
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong, China
| | - Jing Hao
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
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Wang Z, Wen S, Zhong M, Yang Z, Xiong W, Zhang K, Yang S, Li H, Guo S. Epigenetics: Novel crucial approach for osteogenesis of mesenchymal stem cells. J Tissue Eng 2023; 14:20417314231175364. [PMID: 37342486 PMCID: PMC10278427 DOI: 10.1177/20417314231175364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/26/2023] [Indexed: 06/23/2023] Open
Abstract
Bone has a robust regenerative potential, but its capacity to repair critical-sized bone defects is limited. In recent years, stem cells have attracted significant interest for their potential in tissue engineering. Applying mesenchymal stem cells (MSCs) for enhancing bone regeneration is a promising therapeutic strategy. However, maintaining optimal cell efficacy or viability of MSCs is limited by several factors. Epigenetic modification can cause changes in gene expression levels without changing its sequence, mainly including nucleic acids methylation, histone modification, and non-coding RNAs. This modification is believed to be one of the determinants of MSCs fate and differentiation. Understanding the epigenetic modification of MSCs can improve the activity and function of stem cells. This review summarizes recent advances in the epigenetic mechanisms of MSCs differentiation into osteoblast lineages. We expound that epigenetic modification of MSCs can be harnessed to treat bone defects and promote bone regeneration, providing potential therapeutic targets for bone-related diseases.
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Affiliation(s)
- Zhaohua Wang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Si Wen
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Meiqi Zhong
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Ziming Yang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Wei Xiong
- Department of Plastic Surgery, The First Hospital of Shihezi University School of Medicine, Shihezi, China
| | - Kuo Zhang
- College of Humanities and Social Sciences, Dalian Medical University, Dalian, Liaoning Province, China
| | - Shude Yang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Huizheng Li
- Department of Otorhinolaryngology & Head and Neck Surgery, Dalian Friendship Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
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Yan L, Liao L, Su X. Role of mechano-sensitive non-coding RNAs in bone remodeling of orthodontic tooth movement: recent advances. Prog Orthod 2022; 23:55. [PMID: 36581789 PMCID: PMC9800683 DOI: 10.1186/s40510-022-00450-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 11/15/2022] [Indexed: 12/31/2022] Open
Abstract
Orthodontic tooth movement relies on bone remodeling and periodontal tissue regeneration in response to the complicated mechanical cues on the compressive and tensive side. In general, mechanical stimulus regulates the expression of mechano-sensitive coding and non-coding genes, which in turn affects how cells are involved in bone remodeling. Growing numbers of non-coding RNAs, particularly mechano-sensitive non-coding RNA, have been verified to be essential for the regulation of osteogenesis and osteoclastogenesis and have revealed how they interact with signaling molecules to do so. This review summarizes recent findings of non-coding RNAs, including microRNAs and long non-coding RNAs, as crucial regulators of gene expression responding to mechanical stimulation, and outlines their roles in bone deposition and resorption. We focused on multiple mechano-sensitive miRNAs such as miR-21, - 29, -34, -103, -494-3p, -1246, -138-5p, -503-5p, and -3198 that play a critical role in osteogenesis function and bone resorption. The emerging roles of force-dependent regulation of lncRNAs in bone remodeling are also discussed extensively. We summarized mechano-sensitive lncRNA XIST, H19, and MALAT1 along with other lncRNAs involved in osteogenesis and osteoclastogenesis. Ultimately, we look forward to the prospects of the novel application of non-coding RNAs as potential therapeutics for tooth movement and periodontal tissue regeneration.
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Affiliation(s)
- Lichao Yan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Pediatric Dentistry and Engineering Research Center of Oral Translational Medicine and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Li Liao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Pediatric Dentistry and Engineering Research Center of Oral Translational Medicine and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Xiaoxia Su
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Pediatric Dentistry and Engineering Research Center of Oral Translational Medicine and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
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Effects of Resveratrol, Curcumin and Quercetin Supplementation on Bone Metabolism—A Systematic Review. Nutrients 2022; 14:nu14173519. [PMID: 36079777 PMCID: PMC9459740 DOI: 10.3390/nu14173519] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/15/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
Phenolic compounds are natural phytochemicals that have recently reported numerous health benefits. Resveratrol, curcumin, and quercetin have recently received the most attention among these molecules due to their documented antioxidant effects. The review aims to investigate the effects of these molecules on bone metabolism and their role in several diseases such as osteopenia and osteoporosis, bone tumours, and periodontitis. The PubMed/Medline, Web of Science, Google Scholar, Scopus, Cochrane Library, and Embase electronic databases were searched for papers in line with the study topic. According to an English language restriction, the screening period was from January 2012 to 3 July 2022, with the following Boolean keywords: (“resveratrol” AND “bone”); (“curcumin” AND “bone”); (“quercetin” AND “bone”). A total of 36 papers were identified as relevant to the purpose of our investigation. The studies reported the positive effects of the investigated phenolic compounds on bone metabolism and their potential application as adjuvant treatments for osteoporosis, bone tumours, and periodontitis. Furthermore, their use on the titanium surfaces of orthopaedic prostheses could represent a possible application to improve the osteogenic processes and osseointegration. According to the study findings, resveratrol, curcumin, and quercetin are reported to have a wide variety of beneficial effects as supplement therapies. The investigated phenolic compounds seem to positively mediate bone metabolism and osteoclast-related pathologies.
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LncRNA H19 mediates BMP9-induced angiogenesis in mesenchymal stem cells by promoting the p53-Notch1 angiogenic signaling axis. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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36
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Zheng X, Gan S, Su C, Zheng Z, Liao Y, Shao J, Zhu Z, Chen W. Screening and preliminary identification of long non-coding RNAs critical for osteogenic differentiation of human umbilical cord mesenchymal stem cells. Bioengineered 2022; 13:6880-6894. [PMID: 35249446 PMCID: PMC8973756 DOI: 10.1080/21655979.2022.2044274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Human umbilical cord mesenchymal stem cells (hUCMSCs) are attractive therapeutic cells for tissue engineering to treat bone defects. However, how the cells can differentiate into bone remains unclear. Long non-coding RNAs (lncRNAs) are non-coding RNAs that participate in many biological processes, including stem cell differentiation. In this study, we investigated the profiles and functions of lncRNAs in the osteogenic differentiation of hUCMSCs. We identified 343 lncRNAs differentially expressed during osteogenic differentiation, of which 115 were upregulated and 228 were downregulated. We further analyzed these lncRNAs using bioinformatic analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. GO and KEGG pathway analysis showed that ‘intracellular part’ and ‘Phosphatidylinositol signaling system’ were the most correlated molecular function and pathway, respectively. We selected the top 10 upregulated lncRNAs to construct six competing endogenous RNA networks. We validated the impact of the lncRNA H19 on osteogenic differentiation by overexpressing it in hUCMSCs. Overall, our results pave the way to detailed studies of the molecular mechanisms of hUCMSC osteogenic differentiation, and they provide a new theoretical basis to guide the therapeutic application of hUCMSCs.
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Affiliation(s)
- Xiao Zheng
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Pediatric Dentistry, Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, Guangdong, China
| | - Shuaiqi Gan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Cheng Su
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Zheng Zheng
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yihan Liao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Jingjing Shao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Zhimin Zhu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Wenchuan Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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Hao Y, Wang Y, Du M, Wang L, Liu Z, Zhang C, Cao Z, He H. Effects of long noncoding RNA H19 on cementoblast differentiation, mineralisation, and proliferation. Acta Odontol Scand 2022; 80:150-156. [PMID: 34392794 DOI: 10.1080/00016357.2021.1966096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE Cementum which is a layer of thin and bone-like mineralised tissue covering tooth root surface is deposited and mineralised by cementoblasts. Recent studies suggested long noncoding RNA H19 (H19) promotes osteoblast differentiation and matrix mineralisation, however, the effect of H19 on cementoblasts remains unknown. This study aimed to clarify the regulatory effects of H19 on cementoblast differentiation, mineralisation, and proliferation. MATERIAL AND METHODS An immortalised murine cementoblast cell line OCCM-30 was used in this study. H19 expression was examined by real-time quantitative polymerase chain reaction (RT-qPCR) during OCCM-30 cell differentiation. OCCM-30 cells were transfected with lentivirus or siRNA to up-regulate or down-regulate H19, then the levels of runt-related transcription factor 2 (Runx2), osterix (Sp7), alkaline phosphatase (Alpl), bone sialoprotein (Ibsp), osteocalcin (Bglap) were tested by RT-qPCR or western blot. Alizarin red staining, ALP activity assay and MTS assay were performed to determine the mineralisation and proliferation ability of OCCM-30 cells. RESULTS H19 was dramatically increased during OCCM-30 cell differentiation. Overexpression of H19 increased the levels of Runx2, Sp7, Alpl, Ibsp, and Bglap and enhanced ALP activity and the formation of mineral nodules. While down-regulation of H19 suppressed the above cementoblast differentiation genes and inhibited ALP activity and mineral nodule formation. However, the proliferation of OCCM-30 cells was not affected. CONCLUSIONS H19 promotes the differentiation and mineralisation of cementoblasts without affecting cell proliferation.
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Affiliation(s)
- Yunru Hao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Yunlong Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Mingyuan Du
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Leilei Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Zhijian Liu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Chen Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Zhengguo Cao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Hong He
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
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38
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Peng F, Yan S, Liu H, Liu Z, Jiang F, Cao P, Fu R. Roles of LINC01473 and CD74 in osteoblasts in multiple myeloma bone disease. J Investig Med 2022; 70:1301-1307. [PMID: 35145037 PMCID: PMC9240337 DOI: 10.1136/jim-2021-002192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2022] [Indexed: 11/22/2022]
Abstract
The suppression of osteoblast (OB) activity is partially responsible for multiple myeloma (MM) bone disease. Long non-coding RNAs (lncRNAs) play a vital role in bone formation and resorption. However, their functions in OBs from patients with MM have rarely been reported. Through high-throughput sequencing of OBs from patients with MM and healthy controls, we identified several lncRNAs and messenger RNAs (mRNAs) with different expression profile and validated them using quantitative real-time PCR. In total, 22 upregulated and 21 downregulated lncRNAs were found in OBs from patients with MM. Moreover, 18 upregulated protein-coding mRNAs were identified. The expression levels of LINC01473 and its associated co-expression mRNA, CD74, were higher in patients with MM than in healthy controls (p=0.047 and p=0.016, respectively). LINC01473 expression demonstrated a negative correlation with serum interleukin-2 and tumor necrosis factor α levels, whereas the expression of mRNA CD74 was positively associated with serum lactic dehydrogenase in patients with MM. Aberrant expression of lncRNAs and mRNAs was observed in OBs from patients with MM. This study identifies new promising targets for further research on imbalanced bone formation and resorption and MM immune escape.
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Affiliation(s)
- Fengping Peng
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Siyang Yan
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Fengjuan Jiang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Panpan Cao
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
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De la Fuente-Hernandez MA, Sarabia-Sanchez MA, Melendez-Zajgla J, Maldonado-Lagunas V. Role of lncRNAs into Mesenchymal Stromal Cell Differentiation. Am J Physiol Cell Physiol 2022; 322:C421-C460. [PMID: 35080923 DOI: 10.1152/ajpcell.00364.2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Currently, findings support that 75% of the human genome is actively transcribed, but only 2% is translated into a protein, according to databases such as ENCODE (Encyclopedia of DNA Elements) [1]. The development of high-throughput sequencing technologies, computational methods for genome assembly and biological models have led to the realization of the importance of the previously unconsidered non-coding fraction of the genome. Along with this, noncoding RNAs have been shown to be epigenetic, transcriptional and post-transcriptional regulators in a large number of cellular processes [2]. Within the group of non-coding RNAs, lncRNAs represent a fascinating field of study, given the functional versatility in their mode of action on their molecular targets. In recent years, there has been an interest in learning about lncRNAs in MSC differentiation. The aim of this review is to address the signaling mechanisms where lncRNAs are involved, emphasizing their role in either stimulating or inhibiting the transition to differentiated cell. Specifically, the main types of MSC differentiation are discussed: myogenesis, osteogenesis, adipogenesis and chondrogenesis. The description of increasingly new lncRNAs reinforces their role as players in the well-studied field of MSC differentiation, allowing a step towards a better understanding of their biology and their potential application in the clinic.
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Affiliation(s)
- Marcela Angelica De la Fuente-Hernandez
- Facultad de Medicina, Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.,Laboratorio de Epigenética, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Miguel Angel Sarabia-Sanchez
- Facultad de Medicina, Posgrado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Jorge Melendez-Zajgla
- Laboratorio de Genómica Funcional del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
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Yang Z, Feng L, Wang H, Li Y, Lo JHT, Zhang X, Lu X, Wang Y, Lin S, Tortorella MD, Li G. DANCR Mediates the Rescuing Effects of Sesamin on Postmenopausal Osteoporosis Treatment via Orchestrating Osteogenesis and Osteoclastogenesis. Nutrients 2021; 13:4455. [PMID: 34960006 PMCID: PMC8704418 DOI: 10.3390/nu13124455] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/08/2021] [Accepted: 12/11/2021] [Indexed: 02/03/2023] Open
Abstract
As one of the leading causes of bone fracture in postmenopausal women and in older men, osteoporosis worldwide is attracting more attention in recent decades. Osteoporosis is a common disease mainly resulting from an imbalance of bone formation and bone resorption. Pharmaceutically active compounds that both activate osteogenesis, while repressing osteoclastogenesis hold the potential of being therapeutic medications for osteoporosis treatment. In the present study, sesamin, a bioactive ingredient derived from the seed of Sesamum Indicum, was screened out from a bioactive compound library and shown to exhibit dual-regulating functions on these two processes. Sesamin was demonstrated to promote osteogenesis by upregulating Wnt/β-catenin, while repressing osteoclastogenesis via downregulating NF-κB signaling . Furthermore, DANCR was found to be the key regulator in sesamin-mediated bone formation and resorption . In an ovariectomy (OVX)-induced osteoporotic mouse model, sesamin could rescue OVX-induced bone loss and impairment. The increased serum level of DANCR caused by OVX was also downregulated upon sesamin treatment. In conclusion, our results demonstrate that sesamin plays a dual-functional role in both osteogenesis activation and osteoclastogenesis de-activation in a DANCR-dependent manner, suggesting that it may be a possible medication candidate for osteoporotic patients with elevated DNACR expression levels.
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Affiliation(s)
- Zhengmeng Yang
- Stem Cells and Regenerative Medicine Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hospital, Hong Kong, China; (Z.Y.); (H.W.); (Y.L.); (J.H.T.L.); (X.Z.); (X.L.); (S.L.)
| | - Lu Feng
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China; (L.F.); (Y.W.)
| | - Haixing Wang
- Stem Cells and Regenerative Medicine Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hospital, Hong Kong, China; (Z.Y.); (H.W.); (Y.L.); (J.H.T.L.); (X.Z.); (X.L.); (S.L.)
| | - Yucong Li
- Stem Cells and Regenerative Medicine Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hospital, Hong Kong, China; (Z.Y.); (H.W.); (Y.L.); (J.H.T.L.); (X.Z.); (X.L.); (S.L.)
| | - Jessica Hiu Tung Lo
- Stem Cells and Regenerative Medicine Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hospital, Hong Kong, China; (Z.Y.); (H.W.); (Y.L.); (J.H.T.L.); (X.Z.); (X.L.); (S.L.)
| | - Xiaoting Zhang
- Stem Cells and Regenerative Medicine Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hospital, Hong Kong, China; (Z.Y.); (H.W.); (Y.L.); (J.H.T.L.); (X.Z.); (X.L.); (S.L.)
| | - Xuan Lu
- Stem Cells and Regenerative Medicine Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hospital, Hong Kong, China; (Z.Y.); (H.W.); (Y.L.); (J.H.T.L.); (X.Z.); (X.L.); (S.L.)
| | - Yaofeng Wang
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China; (L.F.); (Y.W.)
| | - Sien Lin
- Stem Cells and Regenerative Medicine Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hospital, Hong Kong, China; (Z.Y.); (H.W.); (Y.L.); (J.H.T.L.); (X.Z.); (X.L.); (S.L.)
| | - Micky D. Tortorella
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China; (L.F.); (Y.W.)
| | - Gang Li
- Stem Cells and Regenerative Medicine Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hospital, Hong Kong, China; (Z.Y.); (H.W.); (Y.L.); (J.H.T.L.); (X.Z.); (X.L.); (S.L.)
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Liang W, Shi C, Hong W, Li P, Zhou X, Fu W, Lin L, Zhang J. Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:1351-1363. [PMID: 34853732 PMCID: PMC8608597 DOI: 10.1016/j.omtn.2021.10.028] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 09/06/2021] [Accepted: 10/28/2021] [Indexed: 12/15/2022]
Abstract
Aberrant expression of long non-coding RNAs (lncRNAs) has been reported in multiple cancers. However, the underlying mechanisms mediated by super-enhancers remain elusive. Here we sought to define the role of a novel lncRNA termed lncRNA-DAW in tumorigenesis. Our results revealed that lncRNA-DAW was driven by a liver-specific super-enhancer and transcriptionally activated by HNF4G, leading to frequent elevation in hepatocellular carcinoma (HCC) specimens. Ectopic expression of lncRNA-DAW promoted both in vivo and in vitro tumor growth. By using RNA sequencing, Wnt2 was screened out as a downstream effector of lncRNA-DAW. We next found that lncRNA-DAW physically interacted with EZH2, a negative regulator of Wnt2. This interplay subsequently potentiated CDK1-EZH2 interaction, leading to the phosphorylation and ubiquitination of EZH2. The lncRNA-DAW-mediated EZH2 degradation facilitated the de-repression of Wnt2 transcription, which eventually activated the Wnt/β-catenin pathway. Furthermore, we verified that Wnt2 potentiated in vitro and in vivo cancer cell growth by activating the Wnt/β-catenin pathway. Finally, Wnt2 amplification was confirmed as a common event in liver cancer, and the expression of lncRNA-DAW was positively correlated with Wnt2 in HCC specimens. Collectively, we are the first to identify lncRNA-DAW as a novel candidate oncogene in liver cancer, and this lncRNA may serve as a novel clinical diagnosis biomarker for liver cancer.
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Affiliation(s)
- Weicheng Liang
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China.,Biotherapy Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Chuanjian Shi
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P.R. China.,Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Weilong Hong
- Department of Emergency, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Panlong Li
- Biotherapy Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Xue Zhou
- Department of Ultrasonic Medicine, Guangzhou Women and Children's Medical Center, Guangzhou, P.R. China
| | - Weiming Fu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P.R. China.,Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Lizhu Lin
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Jinfang Zhang
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China.,Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
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Zhou X, Cao H, Wang M, Zou J, Wu W. Moderate-intensity treadmill running relieves motion-induced post-traumatic osteoarthritis mice by up-regulating the expression of lncRNA H19. Biomed Eng Online 2021; 20:111. [PMID: 34794451 PMCID: PMC8600697 DOI: 10.1186/s12938-021-00949-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 11/03/2021] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND The purpose of this study was to explore whether moderate-intensity exercise can alleviate motion-induced post-traumatic osteoarthritis (PTOA) and the expression change of lncRNA H19 during this progression. METHODS Twenty-week-old male C57BL/6 mice were randomly divided into five groups: model control group (MC group, n = 6), treadmill model group (M group, n = 6), rehabilitation control group (RC group, n = 6), treadmill model + rehabilitation training group (M + R group, n = 6) and treadmill model + convalescent group (M + C group, n = 6). Paraffin sections were used to observe the pathological changes in the mouse knee joint in each group. A micro-CT was used to scan the knee joint to obtain the morphological indexes of the tibial plateau bone. Real-time PCR was used to detect the mRNA levels of inflammatory factors, synthetic and catabolic factors in cartilage. RESULTS After high-intensity exercise for 4 weeks, the inflammation and catabolism of the mouse knee cartilage were enhanced, and the anabolism was weakened. Further study showed that these results were partially reversed after 4-week moderate-intensity training. The results of hematoxylin-eosin staining confirmed this finding. Meanwhile, high-intensity exercise reduced the expression of lncRNA H19 in cartilage, while the expression of lncRNA H19 increased after 4 weeks of moderate-intensity exercise. CONCLUSION High-intensity treadmill running can cause injury to the knee cartilage in C57BL/6 mice which leads to PTOA and a decrease of lncRNA H19 expression in cartilage. Moderate-intensity exercise can relieve PTOA and partially reverse lncRNA H19 expression.
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Affiliation(s)
- Xuchang Zhou
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Hong Cao
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Miao Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Jun Zou
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Wei Wu
- School of Kinesiology, Shanghai University of Sport, Shanghai, China.
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Tang W, Liu Q, Tan W, Sun T, Deng Y. LncRNA expression profile analysis of Mg 2+-induced osteogenesis by RNA-seq and bioinformatics. Genes Genomics 2021; 43:1247-1257. [PMID: 34427873 DOI: 10.1007/s13258-021-01140-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/13/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND In recent years, magnesium (Mg) has been extensively studied for manufacturing biodegradable orthopedic devices. Besides other advantages, researches have shown that magnesium-based implants can stimulate osteogenesis thus accelerating orthopedic trauma recovery, but its molecular mechanism is not fully understood. Meanwhile, long non-coding RNA (lncRNA) has been found to play vital role in regulating osteogenic differentiation. OBJECTIVE To explore the role of lncRNA in Mg2+ (magnesium ions)-induced osteogenesis. METHODS The effect of Mg2+ on mBMSCs proliferation was detected by the CCK-8 assay. The optimum concentration of Mg2+ (7.5 mM) in promoting mBMSCs osteogenesis was determined by ALP staining and Alizarin red staining, western blot and RT-qPCR were performed to detect osteogenic markers expressions. The lncRNAs and mRNAs expression profiles of mBMSCs were assessed by RNA-Seq and processed by bioinformatics analysis. The selected lncRNAs expression level was validated by RT-qPCR. RESULTS The effect of Mg2+ in promoting osteogenesis was confirmed and the optimum concentration was determined as 7.5 mM. The lncRNAs and mRNAs differentially expressed between 7.5 mM Mg2+-treated group and control group was detected and functional analysis revealed that their function were associated with osteogenesis. The ceRNA networks were constructed for H19 and Dubr that aberrantly expressed in two groups. The ceRNA networks of selected lncRNAs (H19 and Dubr) were constructed. CONCLUSIONS This study identified H19 and Dubr as osteogenic associated lncRNAs involved in Mg2+-induced osteogenesis, and they might play their roles through lncRNA-miRNA-mRNA axis.
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Affiliation(s)
- Wen Tang
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Qing Liu
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Wei Tan
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Tianshi Sun
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Youwen Deng
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
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Li C, Shangguan Y, Zhu P, Dai W, Tang D, Ou M, Dai Y. Multiomics landscape of the autosomal dominant osteopetrosis type II disease-specific induced pluripotent stem cells. Hereditas 2021; 158:40. [PMID: 34702373 PMCID: PMC8549315 DOI: 10.1186/s41065-021-00204-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 10/08/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Autosomal dominant osteopetrosis type II (ADO2) is a genetically and phenotypically metabolic bone disease, caused by osteoclast abnormalities. The pathways dysregulated in ADO2 could lead to the defects in osteoclast formation and function. However, the mechanism remains elusive. MATERIALS AND METHODS To systematically explore the molecular characterization of ADO2, we performed a multi-omics profiling from the autosomal dominant osteopetrosis type II iPSCs (ADO2-iPSCs) and healthy normal control iPSCs (NC-iPSCs) using whole genome re-sequencing, DNA methylation and N6-methyladenosine (m6A) analysis in this study. RESULTS Totally, we detected 7,095,817 single nucleotide polymorphisms (SNPs) and 1,179,573 insertion and deletions (InDels), 1,001,943 differentially methylated regions (DMRs) and 2984 differential m6A peaks, and the comprehensive multi-omics profile was generated from the two cells. Interestingly, the ISG15 m6A level in ADO2-iPSCs is higher than NC-iPSCs by IGV software, and the differentially expressed m6A-modified genes (DEMGs) were highly enriched in the osteoclast differentiation and p53 signaling pathway, which associated with the development of osteopetrosis. In addition, combining our previously published transcriptome and proteome datasets, we found that the change in DNA methylation levels correlates inversely with some gene expression levels. CONCLUSION Our results indicate that the global multi-omics landscape not only provides a high-quality data resource but also reveals a dynamic pattern of gene expression, and found that the pathogenesis of ADO2 may begin early in life.
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Affiliation(s)
- Chunhong Li
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541199, People's Republic of China
| | - Yu Shangguan
- Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, Guangdong, 518020, People's Republic of China.,Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory of Guilin, NO. 924 Hospital, Guilin, 541002, People's Republic of China
| | - Peng Zhu
- Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, Guangdong, 518020, People's Republic of China
| | - Weier Dai
- College of Natural Science, University of Texas at Austin, Austin, TX, 78712, USA
| | - Donge Tang
- Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, Guangdong, 518020, People's Republic of China.
| | - Minglin Ou
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541199, People's Republic of China.
| | - Yong Dai
- Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, Guangdong, 518020, People's Republic of China.
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Zhang L, Liu T, Wang P, Shen Y, Huang T. Overexpression of Long Noncoding RNA H19 Inhibits Cardiomyocyte Apoptosis in Neonatal Rats with Hypoxic-Ischemic Brain Damage Through the miR-149-5p/LIF/PI3K/Akt Axis. Biopreserv Biobank 2021; 19:376-385. [PMID: 34672722 DOI: 10.1089/bio.2020.0088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hypoxic-ischemic brain damage (HIBD) is a leading cause of fatality and neural system injury in neonates. This study aims to explore the effect of long noncoding RNA H19 on cardiomyocyte apoptosis in neonatal rats with HIBD. The neonatal rat model of HIBD was established. The cerebral infarction volume and apoptosis index of cardiomyocyte increased, while H19 expression decreased in neonatal rats with HIBD. After the lentivirus vector of overexpressed H19 was injected into neonatal rats with HIBD, the cardiomyocyte apoptosis was suppressed; levels of inflammatory factors and oxidative stress injury of myocardial tissues were reduced. The binding relationships between H19 and miR-149-5p, and miR-149-5p and leukemia inhibitory factor (LIF) were predicted by a bioinformatics website and verified using the dual-luciferase reporter gene assay. H19 competitively bound to miR-149-5p to upregulate LIF expression and activate the PI3K/Akt pathway. Moreover, a functional rescue experiment was carried out. Injection of Wortmannin reversed the inhibitory effect of H19 overexpression on cardiomyocyte apoptosis in neonatal rats with HIBD. It could be concluded that H19 competitively bound to miR-149-5p to upregulate LIF expression and activate the PI3K/Akt pathway, thus reducing cardiomyocyte apoptosis in neonatal rats with HIBD. This study may offer new insights for HIBD treatment.
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Affiliation(s)
- Lina Zhang
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Tao Liu
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Ping Wang
- Department of Hand and Foot Surgery, Nanchang Fifth Hospital, Nanchang, P.R. China
| | - Yanhong Shen
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Tao Huang
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
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Bian W, Xiao S, Yang L, Chen J, Deng S. Quercetin promotes bone marrow mesenchymal stem cell proliferation and osteogenic differentiation through the H19/miR-625-5p axis to activate the Wnt/β-catenin pathway. BMC Complement Med Ther 2021; 21:243. [PMID: 34592982 PMCID: PMC8485455 DOI: 10.1186/s12906-021-03418-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 09/17/2021] [Indexed: 01/22/2023] Open
Abstract
Background Quercetin and H19 can promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). However, whether quercetin regulates H19 expression to promote osteogenic differentiation of BMSCs is unclear. Methods BMSC proliferation, matrix mineralization, and alkaline phosphatase (ALP) activity were assessed using the Cell Counting Kit-8, ALP assay kit, and alizarin red staining kit, respectively. Expression of H19, miR-625-5p, BMP-2, osteocalcin, and RUNX2 were measured by qRT-PCR; β-catenin protein level was measured by western blotting. Results Quercetin promoted BMSC proliferation, enhanced ALP activity, and upregulated the expression of BMP-2, osteocalcin, and RUNX2 mRNAs, suggesting that it promoted osteogenic differentiation of BMSCs. Moreover, quercetin increased H19 expression, while the effect of quercetin on BMSCs was reversed by silencing H19 expression. Additionally, miR-625-5p, interacted with H19, was downregulated during quercetin-induced BMSC osteogenic differentiation, which negatively correlated with H19 expression. Silencing miR-625-5p expression promoted BMSC proliferation and osteogenic differentiation, whereas miR-625-5p overexpression weakened the effect of quercetin on BMSCs. Finally, quercetin treatment or downregulation of miR-625-5p expression increased β-catenin protein level in BMSCs. Upregulation or downregulation of miR-625-5p or H19 expression, respectively, inhibited β-catenin protein level in quercetin treated-BMSCs. Conclusion H19 promotes, while miR-625-5p inhibits BMSC osteogenic differentiation. Quercetin activates the Wnt/β-catenin pathway and promotes BMSC osteogenic differentiation via the H19/miR-625-5p axis. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-021-03418-8.
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Affiliation(s)
- Wei Bian
- Department of Traditional Chinese Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), No. 1017, Dongmen North Road, Luohu District, Shenzhen, 518020, China
| | - Shunqiang Xiao
- Department of Traditional Chinese Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), No. 1017, Dongmen North Road, Luohu District, Shenzhen, 518020, China
| | - Lei Yang
- Department of Geriatrics in Luohu Hospital of Traditional Chinese Medicine/Shenzhen Hospital of Shanghai University of traditional Chinese Medicine, Shenzhen, 518000, China
| | - Jun Chen
- Department of Traditional Chinese Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), No. 1017, Dongmen North Road, Luohu District, Shenzhen, 518020, China
| | - Shifang Deng
- Department of Traditional Chinese Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), No. 1017, Dongmen North Road, Luohu District, Shenzhen, 518020, China.
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Chen S, Liu D, Zhou Z, Qin S. Role of long non-coding RNA H19 in the development of osteoporosis. Mol Med 2021; 27:122. [PMID: 34583640 PMCID: PMC8480040 DOI: 10.1186/s10020-021-00386-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 09/22/2021] [Indexed: 12/28/2022] Open
Abstract
Background Osteoporosis is a widespread and serious metabolic bone disease. At present, revealing the molecular mechanisms of osteoporosis and developing effective prevention and treatment methods are of great significance to health worldwide. LncRNA is a non-coding RNA peptide chain with more than 200 nucleotides. Researchers have identified many lncRNAs implicated in the development of diseases and lncRNA H19 is an example. Results A large amount of evidence supports the fact that long non-coding RNA (lncRNA) genes, such as H19, have multiple, far-reaching effects on various biological functions. It has been found that lncRNA H19 has a role in the regulation of different types of cells in the body including the osteoblasts, osteocytes, and osteoclasts found in bones. Therefore, it can be postulated that lncRNA H19 affects the incidence and development of osteoporosis. Conclusion The prospect of targeting lncRNA H19 in the treatment of osteoporosis is promising because of the effects that lncRNA H19 has on the process of osteogenic differentiation. In this review, we summarize the molecular pathways and mechanisms of lncRNA H19 in the pathogenesis of osteoporosis and summarize the research progress of targeting H19 as a treatment option. Research is emerging that explores more effective treatment possibilities for bone metabolism diseases using molecular targets.
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Affiliation(s)
- Senxiang Chen
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
| | - Da Liu
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China.
| | - Zimo Zhou
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
| | - Sen Qin
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
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Long Non-coding RNAs: Potential Players in Cardiotoxicity Induced by Chemotherapy Drugs. Cardiovasc Toxicol 2021; 22:191-206. [PMID: 34417760 DOI: 10.1007/s12012-021-09681-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 07/24/2021] [Indexed: 10/20/2022]
Abstract
One of the most important side effects of chemotherapy is cardiovascular complications, such as cardiotoxicity. Many factors are involved in the pathogenesis of cardiotoxicity; one of the most important of which is long non-coding RNAs (lncRNAs). lncRNA has 200-1000 nucleotides. It is involved in important processes such as cell proliferation, regeneration and apoptosis; today it is used as a prognostic and diagnostic factor. A, various drugs by acting on lncRNAs can affect cells. Therefore, by accurately identifying IncRNAs function, we can play an effective role in preventing the development of cardiotoxicity-induced chemotherapy drugs, and use them as a therapeutic strategy to improve clinical symptoms and increase patient survival.
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Wang L, Qi L. The role and mechanism of long non-coding RNA H19 in stem cell osteogenic differentiation. Mol Med 2021; 27:86. [PMID: 34384352 PMCID: PMC8359617 DOI: 10.1186/s10020-021-00350-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 08/05/2021] [Indexed: 12/14/2022] Open
Abstract
Background In recent years, H19, as one of the most well-known long non-coding RNA, has been reported to play important roles in many biological and physiological processes. H19 has been identified to regulate the osteogenic differentiation of various stem cells in many studies. However, the detailed role and regulation mechanism of H19 was not consistent in the reported studies. Main body of the manuscript In this review article we summarized the effect and mechanism of lncRNA H19 on osteogenic differentiation of various stem cells reported in the published literatures. The role and mechanism of H19, H19 expression changes, effect of H19 on cell proliferation in osteogenic differentiation were respectively reviewed. Conclusions An increasing number of studies have provided evidence that H19 play its role in the regulation of stem cell osteogenic differentiation by different mechanisms. Most of the studies favored the positive regulatory effect of H19 through lncRNA-miRNA pathway. The function and underlying mechanisms by which H19 contributes to osteogenic differentiation require further investigation.
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Affiliation(s)
- Liang Wang
- Department of Orthopaedic Surgery, Qilu Hospital of Shandong University, No.107, Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Lei Qi
- Department of Orthopaedic Surgery, Qilu Hospital of Shandong University, No.107, Wenhua Xi Road, Jinan, 250012, Shandong, China.
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Wang X, He J, Wang H, Zhao D, Geng B, Wang S, An J, Wang C, Han H, Xia Y. Fluid shear stress regulates osteoblast proliferation and apoptosis via the lncRNA TUG1/miR-34a/FGFR1 axis. J Cell Mol Med 2021; 25:8734-8747. [PMID: 34350720 PMCID: PMC8435422 DOI: 10.1111/jcmm.16829] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/11/2021] [Accepted: 07/15/2021] [Indexed: 01/22/2023] Open
Abstract
LncRNAs and microRNAs play critical roles in osteoblast differentiation and bone formation. However, their exact roles in osteoblasts under fluid shear stress (FSS) and the possible mechanisms remain unclear. The aim of this study was to explore whether and how miR‐34a regulates osteoblast proliferation and apoptosis under FSS. In this study, FSS down‐regulated miR‐34a levels of MC3T3‐E1 cells. MiR‐34a up‐regulation attenuated FSS‐induced promotion of proliferation and suppression of apoptosis. Luciferase reporter assay revealed that miR‐34a directly targeted FGFR1. Moreover, miR‐34a regulated osteoblast proliferation and apoptosis via FGFR1. Further, we validated that lncRNA TUG1 acted as a competing endogenous RNA (ceRNA) to interact with miR‐34a and up‐regulate FGFR1 protein expression. Furthermore, lncRNA TUG1 could promote proliferation and inhibit apoptosis. Taken together, our study revealed the key role of the lncRNA TUG1/miR‐34a/FGFR1 axis in FSS‐regulated osteoblast proliferation and apoptosis and may provide potential therapeutic targets for osteoporosis.
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Affiliation(s)
- Xingwen Wang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Jinwen He
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Hong Wang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Dacheng Zhao
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Bin Geng
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Shenghong Wang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Jiangdong An
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Cuifang Wang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Hua Han
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Yayi Xia
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
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