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1
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Zhang X, Liu Q, Zhang J, Song C, Han Z, Wang J, Shu L, Liu W, He J, Wang P. The emerging role of lncRNAs in osteoarthritis development and potential therapy. Front Genet 2023; 14:1273933. [PMID: 37779916 PMCID: PMC10538550 DOI: 10.3389/fgene.2023.1273933] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 09/04/2023] [Indexed: 10/03/2023] Open
Abstract
Osteoarthritis impairs the functions of various joints, such as knees, hips, hands and spine, which causes pain, swelling, stiffness and reduced mobility in joints. Multiple factors, including age, joint injuries, obesity, and mechanical stress, could contribute to osteoarthritis development and progression. Evidence has demonstrated that genetics and epigenetics play a critical role in osteoarthritis initiation and progression. Noncoding RNAs (ncRNAs) have been revealed to participate in osteoarthritis development. In this review, we describe the pivotal functions and molecular mechanisms of numerous lncRNAs in osteoarthritis progression. We mention that long noncoding RNAs (lncRNAs) could be biomarkers for osteoarthritis diagnosis, prognosis and therapeutic targets. Moreover, we highlight the several compounds that alleviate osteoarthritis progression in part via targeting lncRNAs. Furthermore, we provide the future perspectives regarding the potential application of lncRNAs in diagnosis, treatment and prognosis of osteoarthritis.
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Affiliation(s)
- Xiaofeng Zhang
- Department of Traumatology, Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou, Zhejiang, China
| | - Qishun Liu
- Department of Orthopedics, Zhejiang Medical & Health Group Hangzhou Hospital, Hang Gang Hospital, Hangzhou, China
| | - Jiandong Zhang
- Department of Orthopedics and Traumatology, Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou, Zhejiang, China
| | - Caiyuan Song
- Department of Traumatology, Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou, Zhejiang, China
| | - Zongxiao Han
- Department of Traumatology, Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou, Zhejiang, China
| | - Jinjie Wang
- Department of Traumatology, Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou, Zhejiang, China
| | - Lilu Shu
- Zhejiang Zhongwei Medical Research Center, Department of Medicine, Hangzhou, Zhejiang, China
| | - Wenjun Liu
- Zhejiang Zhongwei Medical Research Center, Department of Medicine, Hangzhou, Zhejiang, China
| | - Jinlin He
- Department of Traumatology, Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou, Zhejiang, China
| | - Peter Wang
- Zhejiang Zhongwei Medical Research Center, Department of Medicine, Hangzhou, Zhejiang, China
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2
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Veronesi F, Costa V, Bellavia D, Basoli V, Giavaresi G. Epigenetic Modifications of MiRNAs in Osteoarthritis: A Systematic Review on Their Methylation Levels and Effects on Chondrocytes, Extracellular Matrix and Joint Inflammation. Cells 2023; 12:1821. [PMID: 37508486 PMCID: PMC10377913 DOI: 10.3390/cells12141821] [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: 05/19/2023] [Revised: 06/16/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Osteoarthritis (OA) is a joint disorder characterized by progressive degeneration of cartilage extracellular matrix (ECM), chondrocyte hypertrophy and apoptosis and inflammation. The current treatments mainly concern pain control and reduction of inflammation, but no therapeutic strategy has been identified as a disease-modifying treatment. Therefore, identifying specific biomarkers useful to prevent, treat or distinguish the stages of OA disease has become an immediate need of clinical practice. The role of microRNAs (miRNAs) in OA has been investigated in the last decade, and increasing evidence has emerged that the influence of the environment on gene expression through epigenetic processes contributes to the development, progression and aggressiveness of OA, in particular acting on the microenvironment modulations. The effects of epigenetic regulation, particularly different miRNA methylation during OA disease, were highlighted in the present systematic review. The evidence arising from this study of the literature conducted in three databases (PubMed, Scopus, Web of Science) suggested that miRNA methylation state already strongly impacts OA progression, driving chondrocytes and synoviocyte proliferation, apoptosis, inflammation and ECM deposition. However, the possibility of understanding the mechanism by which different epigenetic modifications of miRNA or pre-miRNA sequences drive the aggressiveness of OA could be the new focus of future investigations.
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Affiliation(s)
- Francesca Veronesi
- Surgical Science and Technologies, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136 Bologna, Italy
| | - Viviana Costa
- Surgical Science and Technologies, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136 Bologna, Italy
| | - Daniele Bellavia
- Surgical Science and Technologies, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136 Bologna, Italy
| | - Valentina Basoli
- Department of Biomedical Engineering, Medical Additive Manufacturing Research Group (SwissMAM), University of Basel, 4123 Allschwil, Switzerland
- Oral and Cranio-Maxillofacial Surgery, University Hospital Basel, 4031 Basel, Switzerland
| | - Gianluca Giavaresi
- Surgical Science and Technologies, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136 Bologna, Italy
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3
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Xiao SQ, Cheng M, Wang L, Cao J, Fang L, Zhou XP, He XJ, Hu YF. The role of apoptosis in the pathogenesis of osteoarthritis. INTERNATIONAL ORTHOPAEDICS 2023:10.1007/s00264-023-05847-1. [PMID: 37294429 DOI: 10.1007/s00264-023-05847-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/17/2023] [Indexed: 06/10/2023]
Abstract
PURPOSE Apoptosis is an important physiological process, making a great difference to development and tissue homeostasis. Osteoarthritis (OA) is a chronic joint disease characterized by degeneration and destruction of articular cartilage and bone hyperplasia. This purpose of this study is to provide an updated review of the role of apoptosis in the pathogenesis of osteoarthritis. METHODS A comprehensive review of the literature on osteoarthritis and apoptosis was performed, which mainly focused on the regulatory factors and signaling pathways associated with chondrocyte apoptosis in osteoarthritis and other pathogenic mechanisms involved in chondrocyte apoptosis. RESULTS Inflammatory mediators such as reactive oxygen species (ROS), nitric oxide (NO), IL-1β, tumor necrosis factor-α (TNF-α), and Fas are closely related to chondrocyte apoptosis. NF-κB signaling pathway, Wnt signaling pathway, and Notch signaling pathway activate proteins and gene targets that promote or inhibit the progression of osteoarthritis disease, including chondrocyte apoptosis and ECM degradation. Long non-coding RNAs (LncRNAs) and microRNAs (microRNAs) have gradually replaced single and localized research methods and become the main research approaches. In addition, the relationship between cellular senescence, autophagy, and apoptosis was also briefly explained. CONCLUSION This review offers a better molecular delineation of apoptotic processes that may help in designing new therapeutic options for OA treatment.
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Affiliation(s)
- Si-Qi Xiao
- Department of Rheumatology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
- Jiangsu Province Hospital of Chinese medicine, Nanjing, 210029, China
| | - Miao Cheng
- Department of Rheumatology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
- Jiangsu Province Hospital of Chinese medicine, Nanjing, 210029, China
| | - Lei Wang
- Jiangsu Province Hospital of Chinese medicine, Nanjing, 210029, China
| | - Jing Cao
- Jiangsu Province Hospital of Chinese medicine, Nanjing, 210029, China
| | - Liang Fang
- Department of Rheumatology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
- Jiangsu Province Hospital of Chinese medicine, Nanjing, 210029, China
| | - Xue-Ping Zhou
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xiao-Jin He
- Department of Rheumatology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
- Jiangsu Province Hospital of Chinese medicine, Nanjing, 210029, China.
| | - Yu-Feng Hu
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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4
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A novel regulator in cancer initiation and progression: long noncoding RNA SHNG9. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 25:1512-1521. [PMID: 36586065 DOI: 10.1007/s12094-022-03060-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/21/2022] [Indexed: 01/01/2023]
Abstract
Cancer has become the most common life-threatening disease in the world. Cancers presenting with advanced stages and metastasis show poor prognosis, even with the application of radiotherapy, surgery, chemotherapy and immunotherapy. It is of great importance to explore novel, efficient biomarkers and their internal mechanisms. Recently, it has been reported that long noncoding RNAs (lncRNAs) play important roles in tumor initiation and progression, influencing downstream mRNAs by interacting with miRNAs and functioning as sponges in competing endogenous RNA (ceRNA) networks. Small nucleolar RNA host gene 9 (SNHG9) binds with miRNAs, inducing miRNA downregulation. The downregulated miRNAs enhance downstream target gene expression via ceRNA networks. Dysregulation of SNHG9 is widely observed in tumors and is associated with clinical prognosis features, which makes it a valuable target for cancer biomarkers and therapeutics. Dysregulated SNHG9 in tumor cells also functions in tumor proliferation, colony formation, migration, invasion and inhibition of apoptosis and tumor cell metabolism. This systematic review of SNHG9 in tumors provides new perspectives on cancer diagnosis and treatment.
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5
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Cai Z, Long T, Zhao Y, Lin R, Wang Y. Epigenetic Regulation in Knee Osteoarthritis. Front Genet 2022; 13:942982. [PMID: 35873487 PMCID: PMC9304589 DOI: 10.3389/fgene.2022.942982] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 06/20/2022] [Indexed: 12/02/2022] Open
Abstract
Osteoarthritis (OA) is a complicated disease with both hereditary and environmental causes. Despite an increase in reports of possible OA risk loci, it has become clear that genetics is not the sole cause of osteoarthritis. Epigenetics, which can be triggered by environmental influences and result in transcriptional alterations, may have a role in OA pathogenesis. The majority of recent research on the epigenetics of OA has been focused on DNA methylation, histone modification, and non-coding RNAs. However, this study will explore epigenetic regulation in OA at the present stage. How genetics, environmental variables, and epigenetics interact will be researched, shedding light for future studies. Their possible interaction and control processes open up new avenues for the development of innovative osteoarthritis treatment and diagnostic techniques.
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Affiliation(s)
| | - Teng Long
- *Correspondence: Teng Long, ; You Wang,
| | | | | | - You Wang
- *Correspondence: Teng Long, ; You Wang,
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6
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Okuyan HM, Begen MA. LncRNAs in Osteoarthritis. Clin Chim Acta 2022; 532:145-163. [PMID: 35667478 DOI: 10.1016/j.cca.2022.05.030] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/29/2022] [Accepted: 05/31/2022] [Indexed: 11/27/2022]
Abstract
Osteoarthritis (OA) is a progressive joint disease that affects millions of older adults around the world. With increasing rates of incidence and prevalence worldwide, OA has become an enormous global socioeconomic burden on healthcare systems. Long non-coding ribonucleic acids (lncRNAs), essential functional molecules in many biological processes, are a group of non-coding RNAs that are greater than approximately 200 nucleotides in length. Fast-growing and recent developments in lncRNA research are captivating and represent a novel and promising field in understanding the complexity of OA pathogenesis. The involvement of lncRNAs in OA's pathological processes and their altered expressions in joint tissues, blood and synovial fluid make them attractive candidates for the diagnosis and treatment of OA. We focus on the recent advances in major regulator mechanisms of lncRNAs in the pathophysiology of OA and discuss potential diagnostic and therapeutic uses of lncRNAs for OA. We investigate how upregulation or downregulation of lncRNAs influences the pathogenesis of OA and how we can use lncRNAs to elucidate the molecular mechanism of OA. Furthermore, we evaluate how we can use lncRNAs as a diagnostic marker or therapeutic target for OA. Our study not only provides a comprehensive review of lncRNAs regarding OA's pathogenesis but also contributes to the elucidation of its molecular mechanisms and to the development of diagnostic and therapeutic approaches for OA.
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Affiliation(s)
- Hamza Malik Okuyan
- Biomedical Engineering, Physiotherapy and Rehabilitation, Faculty of Health Sciences, Sakarya University of Applied Sciences, Sakarya, Turkey; Ivey Business School, Epidemiology and Biostatistics - Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
| | - Mehmet A Begen
- Ivey Business School, Epidemiology and Biostatistics - Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
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7
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Li H, Lian K, Mao J, Huang F, Zhang C, Zang J. LncRNA LEMD1-AS1 relieves chondrocyte inflammation by targeting miR-944/PGAP1 in osteoarthritis. Cell Cycle 2022; 21:2038-2050. [PMID: 35686740 DOI: 10.1080/15384101.2022.2084294] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Osteoarthritis (OA) is a common degenerative disease characterized by reducing articular chondrocytes and destruction of joint matrix, it's detailed pathogenesis remains unclear. Emerging evidences have demonstrated that long non-coding RNAs (lncRNAs) are closely related to the progression of OA. This study aims to explore the expression of long non-coding RNA LEMD1 antisense RNA 1 (LEMD1-AS1) in OA tissues and chondrocytes and investigate the possible mechanisms of LEMD1-AS1 in OA, which will provide a new target for the treatment of OA. In our study, LEMD1-AS1 and post-GPI attachment to protein (PGAP1) were lowly expressed, but miR-944 was highly expressed both in OA tissues and in Lipopolysaccharide (LPS) -treated chondrocytes detected by qRT-PCR. Over-expression of LEMD1-AS1 or down-regulation of miR-944 significantly promoted viability, proliferation and inhibited cell apoptosis, cell cycle arrest and inflammatory responses of chondrocytes treated with LPS by CCK-8, EdU, flow cytometry and an ELISA assay. Over-expression of LEMD1-AS1 or down-regulation of miR-944 remarkably increased the protein levels of PCNA, Ki-67, Cyclin A1, Cyclin B1, Cyclin D2 and Bcl-2, while decreasing the protein levels of p27, Bax, Cleaved-caspase-3 and Cleaved-caspase-9 in chondrocytes treated with LPS. LEMD1-AS1 bound to miR-944 and regulated its expression, and PGAP1 presented as a direct target gene of miR-944, which was confirmed by a dual-luciferase reporter assay. Inhibition of PGAP1 partially restored the effects of LEMD1-AS1/miR-944 on the proliferation, cell apoptosis, cell cycle distribution and inflammatory responses of LPS-treated chondrocytes. To conclude, the LEMD1-AS1/miR-944/PGAP1 axis may be a novel therapeutic candidate to target in OA treatment.
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Affiliation(s)
- Haitao Li
- Department of Joint Surgery, Linyi People's Hospital, Linyi, Shandong, China
| | - Kaihua Lian
- Department of Hematology, Qingdao Central Hospital, Qingdao, Shandong, China
| | - Jianguang Mao
- Department of Orthopaedics, Gaoqing People's Hospital, Zibo, Shandong, China
| | - Fuguo Huang
- Department of Orthopaedics, Zhaoyuan People's Hospital, Yantai, Shandong, China
| | - Chunli Zhang
- Department of Ultrasound, Yucheng People's Hospital, Yucheng, Shandong, China
| | - Jianguo Zang
- The Orthopaedics Department of TCM (Traditional Chinese of Medicine), Beicheng New District Hospital of Linyi People's Hospital, Linyi, Shandong, China
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8
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Ren J, Li Y, Wuermanbieke S, Hu S, Huang G. N 6-methyladenosine (m 6A) methyltransferase METTL3-mediated LINC00680 accelerates osteoarthritis through m 6A/SIRT1 manner. Cell Death Dis 2022; 8:240. [PMID: 35501316 PMCID: PMC9061755 DOI: 10.1038/s41420-022-00890-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/20/2021] [Accepted: 01/25/2022] [Indexed: 01/01/2023]
Abstract
Increasing evidence suggest the biological roles of N6-methyladenosine (m6A) and long noncoding RNAs (lncRNAs) in the bone disease, especially osteoarthritis (OA). However, the interaction of m6A and lncRNA in osteoarthritis is still unclear. Here, we found that a m6A-related lncRNA LINC00680 upregulated in the OA tissue and IL-1β-induced isolated primary chondrocytes. Functionally, in IL-1β-induced chondrocytes, silencing of LINC00680 recovered the proliferation and repressed the extracellular matrix (ECM) degradation. Mechanistically, m6A methyltransferase METTL3 combined tithe the m6A site of LINC00680 to up-regulate its expression. Moreover, LINC00680 interacted with SIRT1 mRNA through binding at m6A site on SIRT1 mRNA 3'-UTR, thereby enhancing the stability of SIRT1 mRNA. Overall, these findings exhibited a role of LINC00680/m6A/SIRT1 mRNA complex in chondrocytes. Taken together, the present study intends to uncover the mechanism by which METTL3-mediated LINC00680 accelerates OA progression, which may provide novel insight for OA.
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Affiliation(s)
- Jiangdong Ren
- Department of Joint Surgery, Center for Orthopaedics Surgery, The Third Affiliated Hospital of Southern Medical University (Academy of Orthopaedics Guangdong Province), Tianhe District, Guangzhou, Guangdong Province, China.,Orthopaedics Hospital of Guangdong Province, Tianhe District, Guangzhou, Guangdong Province, China
| | - Yicheng Li
- Department of Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | | | - Shu Hu
- Department of Joint Surgery, Center for Orthopaedics Surgery, The Third Affiliated Hospital of Southern Medical University (Academy of Orthopaedics Guangdong Province), Tianhe District, Guangzhou, Guangdong Province, China.,Orthopaedics Hospital of Guangdong Province, Tianhe District, Guangzhou, Guangdong Province, China
| | - Guangxin Huang
- Department of Joint Surgery, Center for Orthopaedics Surgery, The Third Affiliated Hospital of Southern Medical University (Academy of Orthopaedics Guangdong Province), Tianhe District, Guangzhou, Guangdong Province, China. .,Orthopaedics Hospital of Guangdong Province, Tianhe District, Guangzhou, Guangdong Province, China.
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9
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Xia K, Yu LY, Huang XQ, Zhao ZH, Liu J. Epigenetic regulation by long noncoding RNAs in osteo-/adipogenic differentiation of mesenchymal stromal cells and degenerative bone diseases. World J Stem Cells 2022; 14:92-103. [PMID: 35126830 PMCID: PMC8788182 DOI: 10.4252/wjsc.v14.i1.92] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/07/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
Bone is a complex tissue that undergoes constant remodeling to maintain homeostasis, which requires coordinated multilineage differentiation and proper proliferation of mesenchymal stromal cells (MSCs). Mounting evidence indicates that a disturbance of bone homeostasis can trigger degenerative bone diseases, including osteoporosis and osteoarthritis. In addition to conventional genetic modifications, epigenetic modifications (i.e., DNA methylation, histone modifications, and the expression of noncoding RNAs) are considered to be contributing factors that affect bone homeostasis. Long noncoding RNAs (lncRNAs) were previously regarded as 'transcriptional noise' with no biological functions. However, substantial evidence suggests that lncRNAs have roles in the epigenetic regulation of biological processes in MSCs and related diseases. In this review, we summarized the interactions between lncRNAs and epigenetic modifiers associated with osteo-/adipogenic differentiation of MSCs and the pathogenesis of degenerative bone diseases and highlighted promising lncRNA-based diagnostic and therapeutic targets for bone diseases.
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Affiliation(s)
- Kai Xia
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li-Yuan Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin-Qi Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zhi-He Zhao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jun Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China.
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10
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Kong H, Sun ML, Zhang XA, Wang XQ. Crosstalk Among circRNA/lncRNA, miRNA, and mRNA in Osteoarthritis. Front Cell Dev Biol 2022; 9:774370. [PMID: 34977024 PMCID: PMC8714905 DOI: 10.3389/fcell.2021.774370] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Osteoarthritis (OA) is a joint disease that is pervasive in life, and the incidence and mortality of OA are increasing, causing many adverse effects on people's life. Therefore, it is very vital to identify new biomarkers and therapeutic targets in the clinical diagnosis and treatment of OA. ncRNA is a nonprotein-coding RNA that does not translate into proteins but participates in protein translation. At the RNA level, it can perform biological functions. Many studies have found that miRNA, lncRNA, and circRNA are closely related to the course of OA and play important regulatory roles in transcription, post-transcription, and post-translation, which can be used as biological targets for the prevention, diagnosis, and treatment of OA. In this review, we summarized and described the various roles of different types of miRNA, lncRNA, and circRNA in OA, the roles of different lncRNA/circRNA-miRNA-mRNA axis in OA, and the possible prospects of these ncRNAs in clinical application.
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Affiliation(s)
- Hui Kong
- College of Kinesiology, Shenyang Sport University, Shenyang, China
| | - Ming-Li Sun
- College of Kinesiology, Shenyang Sport University, Shenyang, China
| | - Xin-An Zhang
- College of Kinesiology, Shenyang Sport University, Shenyang, China
| | - Xue-Qiang Wang
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China.,Department of Rehabilitation Medicine, Shanghai Shangti Orthopaedic Hospital, Shanghai, China
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11
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Ghafouri-Fard S, Poulet C, Malaise M, Abak A, Mahmud Hussen B, Taheriazam A, Taheri M, Hallajnejad M. The Emerging Role of Non-Coding RNAs in Osteoarthritis. Front Immunol 2021; 12:773171. [PMID: 34912342 PMCID: PMC8666442 DOI: 10.3389/fimmu.2021.773171] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/10/2021] [Indexed: 12/16/2022] Open
Abstract
Osteoarthritis (OS) is the most frequent degenerative condition in the joints, disabling many adults. Several abnormalities in the articular cartilage, subchondral bone, synovial tissue, and meniscus have been detected in the course of OA. Destruction of articular cartilage, the formation of osteophytes, subchondral sclerosis, and hyperplasia of synovial tissue are hallmarks of OA. More recently, several investigations have underscored the regulatory roles of non-coding RNAs (ncRNAs) in OA development. Different classes of non-coding RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), have been reported to affect the development of OA. The expression level of these transcripts has also been used as diagnostic tools in OA. In the present article, we aimed at reporting the role of these transcripts in this process. We need to give a specific angle on the pathology to provide meaningful thoughts on it.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Christophe Poulet
- Department of Rheumatology, University Hospital of Liège (CHULiege), Liège, Belgium
- Fibropôle Research Group, University Hospital of Liège (CHULiege), Liège, Belgium
- GIGA-I3 Research Group, GIGA Institute, University of Liège (ULiege) and University Hospital of Liège (CHULiege), Liège, Belgium
| | - Michel Malaise
- Department of Rheumatology, University Hospital of Liège (CHULiege), Liège, Belgium
- Fibropôle Research Group, University Hospital of Liège (CHULiege), Liège, Belgium
- GIGA-I3 Research Group, GIGA Institute, University of Liège (ULiege) and University Hospital of Liège (CHULiege), Liège, Belgium
| | - Atefe Abak
- Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Afshin Taheriazam
- Department of Orthopedics, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
- *Correspondence: Mohammad Taheri, ; Mohammad Hallajnejad,
| | - Mohammad Hallajnejad
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Mohammad Taheri, ; Mohammad Hallajnejad,
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12
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Ali SA, Peffers MJ, Ormseth MJ, Jurisica I, Kapoor M. The non-coding RNA interactome in joint health and disease. Nat Rev Rheumatol 2021; 17:692-705. [PMID: 34588660 DOI: 10.1038/s41584-021-00687-y] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2021] [Indexed: 02/07/2023]
Abstract
Non-coding RNAs have distinct regulatory roles in the pathogenesis of joint diseases including osteoarthritis (OA) and rheumatoid arthritis (RA). As the amount of high-throughput profiling studies and mechanistic investigations of microRNAs, long non-coding RNAs and circular RNAs in joint tissues and biofluids has increased, data have emerged that suggest complex interactions among non-coding RNAs that are often overlooked as critical regulators of gene expression. Identifying these non-coding RNAs and their interactions is useful for understanding both joint health and disease. Non-coding RNAs regulate signalling pathways and biological processes that are important for normal joint development but, when dysregulated, can contribute to disease. The specific expression profiles of non-coding RNAs in various disease states support their roles as promising candidate biomarkers, mediators of pathogenic mechanisms and potential therapeutic targets. This Review synthesizes literature published in the past 2 years on the role of non-coding RNAs in OA and RA with a focus on inflammation, cell death, cell proliferation and extracellular matrix dysregulation. Research to date makes it apparent that 'non-coding' does not mean 'non-essential' and that non-coding RNAs are important parts of a complex interactome that underlies OA and RA.
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Affiliation(s)
- Shabana A Ali
- Bone and Joint Center, Department of Orthopaedic Surgery, Henry Ford Health System, Detroit, MI, USA. .,Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI, USA.
| | - Mandy J Peffers
- Department of Musculoskeletal Biology, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Michelle J Ormseth
- Department of Research and Development, Veterans Affairs Medical Center, Nashville, TN, USA.,Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Igor Jurisica
- Osteoarthritis Research Program, Division of Orthopaedics, Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.,Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Mohit Kapoor
- Osteoarthritis Research Program, Division of Orthopaedics, Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada. .,Department of Surgery and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
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Visconti VV, Cariati I, Fittipaldi S, Iundusi R, Gasbarra E, Tarantino U, Botta A. DNA Methylation Signatures of Bone Metabolism in Osteoporosis and Osteoarthritis Aging-Related Diseases: An Updated Review. Int J Mol Sci 2021; 22:ijms22084244. [PMID: 33921902 PMCID: PMC8072687 DOI: 10.3390/ijms22084244] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 01/03/2023] Open
Abstract
DNA methylation is one of the most studied epigenetic mechanisms that play a pivotal role in regulating gene expression. The epigenetic component is strongly involved in aging-bone diseases, such as osteoporosis and osteoarthritis. Both are complex multi-factorial late-onset disorders that represent a globally widespread health problem, highlighting a crucial point of investigations in many scientific studies. In recent years, new findings on the role of DNA methylation in the pathogenesis of aging-bone diseases have emerged. The aim of this systematic review is to update knowledge in the field of DNA methylation associated with osteoporosis and osteoarthritis, focusing on the specific tissues involved in both pathological conditions.
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Affiliation(s)
- Virginia Veronica Visconti
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (V.V.V.); (I.C.); (S.F.); (A.B.)
- Department of Orthopaedics and Traumatology, “Policlinico Tor Vergata” Foundation, Viale Oxford 81, 00133 Rome, Italy; (R.I.); (E.G.)
| | - Ida Cariati
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (V.V.V.); (I.C.); (S.F.); (A.B.)
- Department of Orthopaedics and Traumatology, “Policlinico Tor Vergata” Foundation, Viale Oxford 81, 00133 Rome, Italy; (R.I.); (E.G.)
| | - Simona Fittipaldi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (V.V.V.); (I.C.); (S.F.); (A.B.)
| | - Riccardo Iundusi
- Department of Orthopaedics and Traumatology, “Policlinico Tor Vergata” Foundation, Viale Oxford 81, 00133 Rome, Italy; (R.I.); (E.G.)
| | - Elena Gasbarra
- Department of Orthopaedics and Traumatology, “Policlinico Tor Vergata” Foundation, Viale Oxford 81, 00133 Rome, Italy; (R.I.); (E.G.)
| | - Umberto Tarantino
- Department of Orthopaedics and Traumatology, “Policlinico Tor Vergata” Foundation, Viale Oxford 81, 00133 Rome, Italy; (R.I.); (E.G.)
- Department of Clinical Science and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
- Correspondence:
| | - Annalisa Botta
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (V.V.V.); (I.C.); (S.F.); (A.B.)
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14
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Wang L, Huang Q, Lin Q, Chen L, Shi Q. Knockdown of long non-coding RNA small nucleolar RNA host gene 9 or hexokinase 2 both suppress endometrial cancer cell proliferation and glycolysis. J Obstet Gynaecol Res 2021; 47:2196-2203. [PMID: 33821518 DOI: 10.1111/jog.14777] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 03/02/2021] [Accepted: 03/13/2021] [Indexed: 01/19/2023]
Abstract
AIM Endometrial cancer (EC) is a common type of malignant gynecological cancer. Small nucleolar RNA host gene 9 (SNHG9) has been discovered to serve a role in several types of cancer; however, the role of SNHG9 in EC remains unclear. The present study aimed to investigate the effects of lncRNA SNHG9 on cell proliferation and glycolysis in EC cells. METHODS SNHG9 and hexokinase 2 (HK2) mRNA expression levels were measured by reverse transcription-quantitative PCR. Glucose consumption and lactate production were detected by the glycolysis cell-based assay kit. Cell Counting Kit-8 and colony formation assays were conducted to detect cell proliferation. The knockdown experiments of SNHG9 and HK2 were carried out by transfection of corresponding small interference RNAs (siRNA). The SNHG9-overexpressed plasmid was transfected into the cells to upregulate SNHG9. HK2 protein levels were analyzed by western blotting assay. RESULTS SNHG9 expression levels were significantly upregulated in EC tissues and cells. The knockdown of SNHG9 subsequently effectively attenuated cell proliferation and glycolysis in vitro, while SNHG9 overexpression reported the opposite effects. Notably, the transfection of 2-DG partially reversed the promoting effect of SNHG9 on glycolysis. Downregulation of HK2 markedly decreased cell proliferation and glycolysis in EC cells antagonized SNHG9. CONCLUSION Either downregulation of SNHG9 or HK2 inhibits EC cell proliferation and glycolysis via repressing EC cell proliferation and glycolysis.
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Affiliation(s)
- Lianhua Wang
- Department of Gynecology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Qiming Huang
- Department of Imaging, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Qingqing Lin
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Lvxuan Chen
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Qiyang Shi
- Department of Gynecology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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15
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Fu Q, Zhu J, Wang B, Wu J, Li H, Han Y, Xiang D, Chen Y, Li L. LINC02288 promotes chondrocyte apoptosis and inflammation through miR-374a-3p targeting RTN3. J Gene Med 2021; 23:e3314. [PMID: 33491257 DOI: 10.1002/jgm.3314] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/06/2021] [Accepted: 01/15/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Dysregulation of long non-coding RNAs (lncRNAs) is related to the occurrence of osteoarthritis (OA). In the present study, we explored the role of LINC02288 and its regulatory mechanism in OA development. METHODS GSE113825 was obtained from Gene Expression Omnibus (GEO) database and analyzed to identify the differentially expressed lncRNAs in OA. Gene enrichment analyses and Kyoto Encyclopedia of Genes and Genomes biological process analysis were performed through Metascape (http://metascape.org/gp). The interactions among LINC02288, miR-374a-3p and RTN3 were determined using RNA immunoprecipitation (RIP) assays and dual luciferase reporter assays. Chondrocyte apoptosis was examined using flow cytometry. Western blot assays were conducted to assess the pro-apoptotic and anti-apoptotic markers. RESULTS We identified a total of 4,491 differentially expressed lncRNAs. We focused on LINC02288 as the top-ranked up-regulated lncRNA in OA as indicated by a significant p-value. LINC02288 was significantly up-regulated, which was further verified by a real-time polymerase chain reaction. Down-regulation of LINC02288 significantly reduced the apoptosis of OA chondrocytes induced by interleukin-1β and the production of pro-inflammatory cytokines. These effects were further verified in an OA rat model. An RIP assay and dual luciferase assay further confirmed that LINC02288 served as a sponge of miR-374a-3p. Moreover, the overexpression of RTN3 could partially reverse the effects of LINC02288 knockdown, mediating inhibitory effects on chondrocyte apoptosis and the inflammatory response. Down-regulation of LINC02288 alleviated OA development in an in vivo OA animal model. CONCLUSIONS Our findings indicate that LINC02288 contributes to OA progression by targeting the miR-374a-3p/RTN3 axis, which might provide a promising molecular therapy strategy for OA.
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Affiliation(s)
- Qiwei Fu
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jun Zhu
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Bo Wang
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jun Wu
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Haobo Li
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yaguang Han
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Dong Xiang
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yi Chen
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Lexiang Li
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
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16
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Ma X, Liu L. Knockdown of FAM225B inhibits the progression of the hypertrophic scar following glaucoma surgery by inhibiting autophagy. Mol Med Rep 2021; 23:204. [PMID: 33495826 PMCID: PMC7821338 DOI: 10.3892/mmr.2021.11843] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 12/18/2020] [Indexed: 12/16/2022] Open
Abstract
The formation of a hypertrophic scar (HS) may lead to failure of glaucoma surgery. Long non-coding RNAs (lncRNAs) are involved in the formation of HSs. Moreover, family with sequence similarity 225 member B (FAM225B) is upregulated in HS. However, the role of the lncRNA FAM225B in HS remains unknown. Thus, the present study aimed to investigate the function of FAM225B in HS. Scar fibroblasts were isolated from patients who had undergone glaucoma surgery. Western blotting was used to detect the expressions of Bax, Bcl-2, cleaved caspase 3, p62, ATG7 and Beclin 1, and reverse transcription-quantitative PCR (RT-qPCR) were conducted to determine the level of FAM225B in scar fibroblasts. Microtubule associated protein 1 light chain 3 α staining was performed to examine autophagosomes in scar fibroblasts. Furthermore, cell proliferation was evaluated via 5-ethynyl-2′-deoxyuridine staining. Flow cytometry was conducted to determine cell apoptosis and the levels of reactive oxygen species (ROS) in scar fibroblasts. The cell migratory ability was assessed using a Transwell assay. The results demonstrated that FAM225B knockdown significantly attenuated scar fibroblast proliferation and induced apoptosis. Additionally, transfection of scar fibroblasts with FAM225B small interfering RNA (siRNA) significantly increased the ROS levels and significantly decreased the migration of scar fibroblasts. The FAM225B overexpression-induced increase of scar fibroblast proliferation and migration was significantly reversed by 3-methyladenine administration. The results suggested that knockdown of FAM225B significantly inhibited the proliferation of scar fibroblasts by inhibiting autophagy. Therefore, knockdown of FAM225B could inhibit scar fibroblast proliferation after glaucoma surgery by inhibiting autophagy. These findings may provide a novel perspective of developing treatment strategy for the patients with HSs after glaucoma surgery.
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Affiliation(s)
- Xianpeng Ma
- Department of Dermatology, Affiliated Hospital of Beihua University, Jilin, Jilin 132001, P.R. China
| | - Lili Liu
- Department of Dermatology, Affiliated Hospital of Beihua University, Jilin, Jilin 132001, P.R. China
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Metformin-Induced MicroRNA-34a-3p Downregulation Alleviates Senescence in Human Dental Pulp Stem Cells by Targeting CAB39 through the AMPK/mTOR Signaling Pathway. Stem Cells Int 2021; 2021:6616240. [PMID: 33505470 PMCID: PMC7806386 DOI: 10.1155/2021/6616240] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/02/2020] [Accepted: 12/16/2020] [Indexed: 12/15/2022] Open
Abstract
Dental pulp stem cells (DPSCs) are ideal seed cells for the regeneration of dental tissues. However, DPSC senescence restricts its clinical applications. Metformin (Met), a common prescription drug for type 2 diabetes, is thought to influence the aging process. This study is aimed at determining the effects of metformin on DPSC senescence. Young and aging DPSCs were isolated from freshly extracted human teeth. Flow cytometry confirmed that DPSCs expressed characteristic surface antigen markers of mesenchymal stem cells (MSCs). Cell Counting Kit-8 (CCK-8) assay showed that a concentration of 100 μM metformin produced the highest increase in the proliferation of DPSCs. Metformin inhibited senescence in DPSCs as evidenced by senescence-associated β-galactosidase (SA-β-gal) staining and the expression levels of senescence-associated proteins. Additionally, metformin significantly suppressed microRNA-34a-3p (miR-34a-3p) expression, elevated calcium-binding protein 39 (CAB39) expression, and activated the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway. Dual-luciferase reporter assay confirmed that CAB39 is a direct target for miR-34a-3p. Furthermore, transfection of miR-34a-3p mimics promoted the senescence of DPSCs, while metformin treatment or Lenti-CAB39 transfection inhibited cellular senescence. In conclusion, these results indicated that metformin could alleviate the senescence of DPSCs by downregulating miR-34a-3p and upregulating CAB39 through the AMPK/mTOR signaling pathway. This study elucidates on the inhibitory effect of metformin on DPSC senescence and its potential as a therapeutic target for senescence treatment.
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