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Wen R, Huang R, Xu K, Yi X. Insights into the role of histone lysine demethylases in bone homeostasis and skeletal diseases: A review. Int J Biol Macromol 2025; 306:141807. [PMID: 40054804 DOI: 10.1016/j.ijbiomac.2025.141807] [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: 02/14/2024] [Revised: 03/03/2025] [Accepted: 03/04/2025] [Indexed: 05/11/2025]
Abstract
Histone lysine demethylases (KDMs), as important epigenetic regulators, are involved in various biological processes such as energy metabolism, apoptosis, and autophagy. Recent research shows that KDMs activate or silence downstream target genes by removing lysine residues from histone tails, and participate in the regulation of bone marrow mesenchymal stem cells (BM-MSCs), osteoblasts (OB), osteoclasts (OC), chondrocytes and other skeletal cell development, differentiation and formation. Moreover, several members of the KDM family affect the occurrence and development of bone diseases such as osteoporosis (OP), osteoarthritis (OA), osteosarcoma (OS), by regulating target genes. Specific regulation mechanisms of KDMs suggest new strategies for bone disease treatment and prevention. Despite the unique function and importance of KDMs in the skeletal system, previous studies have never systematically summarized their specific role, molecular mechanism, and clinical treatment in bone physiology and pathology. Therefore, this review summarises the expression pattern, intracellular signal transduction, and mechanism of action of the KDM family in several bone physiological and pathological conditions, aiming to highlight the important role of KDMs in bone diseases and provide a reference for the future treatment of bone diseases.
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Affiliation(s)
- Ruiming Wen
- School of Sports Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Ruiqi Huang
- School of Sports Health, Shenyang Sport University, Shenyang, Liaoning, China; School of Physical Education, Liaoning Normal University, Dalian, Liaoning, China
| | - Ke Xu
- School of Sports Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Xuejie Yi
- School of Sports Health, Shenyang Sport University, Shenyang, Liaoning, China.
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2
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Morici L, Allémann E, Jordan O, Nikolić I. Promising LOX proteins for cartilage-targeting osteoarthritis therapy. Pharmacol Res 2025; 212:107627. [PMID: 39875019 DOI: 10.1016/j.phrs.2025.107627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/15/2025] [Accepted: 01/24/2025] [Indexed: 01/30/2025]
Abstract
Osteoarthritis (OA) is the most affected joint disease worldwide, touching millions of people every year. It is caused by a progressive degeneration of articular cartilage, causing pain and limited mobility. Among the pathways involved in cartilage homeostasis, "LOX" proteins (referring to three distinct protein families, very often confused in the literature) play a prominent role. The lipoxygenase enzyme family is involved in the inflammatory process of OA by inducing the production of several pro-inflammatory leukotrienes. Lectin-like oxidized low-density lipoprotein family are receptors located at the surface of chondrocytes, which interact with their ligand, ox-LDL, activating several catabolic pathways involved in OA pathophysiology. Finally, lysyl oxidase and lysyl oxidase-like are enzymes expressed intracellularly (in chondrocytes' cytoplasm) involved in elastin biosynthesis and collagen cross-linking in cartilage extracellular matrix. EMA and FDA have not yet approved any drug targeting the LOX proteins. In particular, today lysyl oxidase-like 2 is considered as a new promising target for OA modifying therapy. This review clarifies the main roles of different LOX proteins involved in the progression of OA. Potential LOX inhibitoion strategies for drug development in advanced OA therapy, particularly for local intraarticular delivery, were listed and discussed for each target type. This review, therefore, proposes promising strategies for future drug development in OA treatment.
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Affiliation(s)
- Luca Morici
- School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland
| | - Eric Allémann
- School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland
| | - Olivier Jordan
- School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland
| | - Ines Nikolić
- School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland.
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Yang J, Tan F, Chen Y, Li X, Yuan C. The emerging role of long non-coding RNA SOX2-OT in cancers and non-malignant diseases. J Physiol Biochem 2025; 81:57-83. [PMID: 39702742 DOI: 10.1007/s13105-024-01059-2] [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: 01/19/2024] [Accepted: 11/02/2024] [Indexed: 12/21/2024]
Abstract
SOX2 overlapping transcript (SOX2-OT) is a long non-coding RNA located at chromosome 3q26.33 in humans. Convincing data confirm that SOX2-OT is evolutionarily conserved and plays a significant role in various malignant and non-malignant diseases. In most cancers, the upregulation of SOX2-OT acts as an oncogenic factor, strongly correlating with tumor risk, adverse clinicopathological features, and poor prognosis. Mechanistically, SOX2-OT is regulated by seven transcription factors and influences cellular behavior by modulating SOX2 expression, competitively binding 20 types of miRNAs, stabilizing protein expression, or promoting protein ubiquitination. It also participates in epigenetic modifications and activates multiple signaling pathways to regulate cancer cell proliferation, apoptosis, migration, invasion, autophagy, immune evasion, and resistance to chemotherapy/targeted therapies. Additionally, SOX2-OT triggers apoptosis, oxidative stress, and inflammatory responses, contributing to neurodevelopmental disorders, cardiovascular diseases, and diabetes-related conditions. Genetic polymorphisms of SOX2-OT have also been linked to breast cancer, gastric cancer, recurrent miscarriage, sepsis, and eating disorders in patients with bipolar disorder. This review provides an overview of recent research progress on SOX2-OT in human diseases, highlights its substantial potential as a prognostic and diagnostic biomarker, and explores its future clinical applications.
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Affiliation(s)
- Jingjie Yang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Fangshun Tan
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Yaohui Chen
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Xiaolan Li
- The Second People's Hospital of China Three Gorges University, Yichang, 443002, China.
- The Second People's Hospital of Yichang, Hubei, China.
| | - Chengfu Yuan
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, 443002, China.
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
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Ma Y, Lv W, Guo Y, Yin T, Bai Y, Liu Z, Chen C, WenjuanYang, Feng J, Qian W, Tang R, Su Y, Shan S, Dong H, Bao Y, Qu L. Histone demethylases in autophagy and inflammation. Cell Commun Signal 2025; 23:24. [PMID: 39806430 PMCID: PMC11727796 DOI: 10.1186/s12964-024-02006-w] [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: 06/21/2024] [Accepted: 12/20/2024] [Indexed: 01/16/2025] Open
Abstract
Autophagy dysfunction is associated with changes in autophagy-related genes. Various factors are connected to autophagy, and the mechanism regulating autophagy is highly complicated. Epigenetic changes, such as aberrant expression of histone demethylase, are actively associated not only with oncogenesis but also with inflammatory responses. Among post-translational modifications, histone lysine methylation holds significant importance. There are over 30 members of histone lysine demethylases (KDMs), which act as epigenetic regulators in physiological processes and diseases. Importantly, KDMs are abnormally expressed in the regulation of cellular autophagy and inflammation, representing a crucial mechanism affecting inflammation-related diseases. This article reviewed the function of KDMs proteins in autophagy and inflammation. Specifically, It focused on the specific regulatory mechanisms underlying the activation or inhibition of autophagy, as well as their abnormal expression in inflammatory responses. By analyzing each KDM in epigenetic modification, this review provides a reliable theoretical basis for clinical decision marking regarding autophagy abnormalities and inflammatory diseases.
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Affiliation(s)
- Yaoyao Ma
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Hubei, 437000, China
- School of Basic Medical Sciences, Hubei University of Science and Technology, Hubei, 437000, China
| | - Wenting Lv
- 3Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Hubei, 430071, China
| | - Yi Guo
- School of Basic Medical Sciences, Hubei University of Science and Technology, Hubei, 437000, China
| | - Tong Yin
- 3Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Hubei, 430071, China
| | - Yujie Bai
- Department of Scientific Research and Education, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330000, China
| | - Ziqi Liu
- 3Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Hubei, 430071, China
| | - Chao Chen
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - WenjuanYang
- 3Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Hubei, 430071, China
| | - Jiayi Feng
- 3Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Hubei, 430071, China
| | - Wenbin Qian
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Hubei, 437000, China
| | - Ruiling Tang
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Hubei, 437000, China
| | - Yanting Su
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Hubei, 437000, China
| | - Shigang Shan
- School of Public Health and Nursing, Hubei University of Science and Technology, Hubei, 437000, China
| | - Huifen Dong
- 3Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Hubei, 430071, China.
| | - Yongfen Bao
- School of Basic Medical Sciences, Hubei University of Science and Technology, Hubei, 437000, China.
| | - Lihua Qu
- School of Basic Medical Sciences, Hubei University of Science and Technology, Hubei, 437000, China.
- 3Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Hubei, 430071, China.
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Park SH, Choi SH, Park HY, Ko J, Yoon JS. Role of Lysyl Oxidase-Like Protein 3 in the Pathogenesis of Graves' Orbitopathy in Orbital Fibroblasts. Invest Ophthalmol Vis Sci 2024; 65:33. [PMID: 39546293 DOI: 10.1167/iovs.65.13.33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024] Open
Abstract
Purpose The lysyl oxidase (LOX) family has been implicated in the pathogenesis of diseases caused by inflammation and fibrosis. Therefore, we aimed to examine the role of lysyl oxidase-like protein 3 (LOXL3) in Graves' orbitopathy (GO) pathogenesis and its potential as a treatment target. Methods Quantitative real-time polymerase chain reaction compared the transcript levels of the five LOX family subtypes in orbital tissue explants obtained from patients with GO (n = 18) and healthy controls (n = 15). The effects of LOXL3 inhibition on interleukin (IL)-1β-induced proinflammatory cytokines, transforming growth factor (TGF)-β-induced profibrotic proteins, intracellular signaling molecules, and adipogenic markers were evaluated using Western blotting. Adipogenic differentiation was identified using Oil Red O staining. Results LOX and LOXL3 transcript levels were high in GO tissues. Stimulation with IL-1β, TGF-β, and insulin-like growth factor-1 significantly increased LOXL3 messenger RNA expression in GO fibroblasts. Furthermore, silencing LOXL3 attenuated the IL-1β-induced production of proinflammatory cytokines (IL-6, IL-8, and intercellular adhesion molecule-1) and TGF-β-induced production of profibrotic proteins (fibronectin, collagen 1α, and alpha-smooth muscle actin). It also reduced the IL-1β or TGF-β-induced expression of phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells, protein kinase B, extracellular signal-regulated kinase, and c-Jun N-terminal kinase. Additionally, LOXL3 silencing suppressed adipocyte differentiation and the expression of adipogenic transcription factors (leptin, AP-2, peroxisome proliferator-activated receptor gamma, and CCAAT/enhancer-binding protein). Conclusions LOXL3 is crucial in GO pathogenesis. LOXL3 inhibition reduced inflammatory cytokine production, fibrotic protein expression, and fibroblast differentiation into adipocytes. This study highlights LOXL3 as a potential therapeutic target for GO.
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Affiliation(s)
| | - Soo Hyun Choi
- Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun Young Park
- Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea
| | - JaeSang Ko
- Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Sook Yoon
- Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea
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Yousefnia S. A comprehensive review on lncRNA LOXL1-AS1: molecular mechanistic pathways of lncRNA LOXL1-AS1 in tumorigenicity of cancer cells. Front Oncol 2024; 14:1384342. [PMID: 39136001 PMCID: PMC11317273 DOI: 10.3389/fonc.2024.1384342] [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: 02/09/2024] [Accepted: 07/15/2024] [Indexed: 08/15/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) are versatile RNAs that regulate various cellular processes, such as gene regulation, by acting as signals, decoys, guides, and scaffolds. A novel recognized lncRNA, LOXL1-antisense RNA 1 (LOXL1-AS1), is dysregulated in some diseases, including cancer, and acts as an oncogenic lncRNA in many types of cancer cells. Upregulation of LOXL1-AS1 has been involved in proliferation, migration, metastasis, and EMT, as well as inhibiting apoptosis in cancer cells. Most importantly, the malignant promoting activity of LOXL1-AS1 can be mostly mediated by sequestering specific miRNAs and inhibiting their binding to the 3´UTR of their target mRNAs, thereby indirectly regulating gene expression. Additionally, LOXL1-AS1 can decoy transcription factors and proteins and prevent their binding to their regulatory regions, inhibiting their mechanistic activity on the regulation of gene expression and signaling pathways. This review presents the mechanistic pathways of the oncogenic role of LOXL1-AS1 by modulating its target miRNAs and proteins in various cancer cells. Having information about the molecular mechanisms regulated by LOXL1-AS1 in cancer cells can open ways to find out particular prognostic biomarkers, as well as discover novel therapeutic approaches for different types of cancer.
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Affiliation(s)
- Saghar Yousefnia
- Department of Cell and Molecular Biology, Semnan University, Semnan, Iran
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Shakeri M, Aminian A, Mokhtari K, Bahaeddini M, Tabrizian P, Farahani N, Nabavi N, Hashemi M. Unraveling the molecular landscape of osteoarthritis: A comprehensive review focused on the role of non-coding RNAs. Pathol Res Pract 2024; 260:155446. [PMID: 39004001 DOI: 10.1016/j.prp.2024.155446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024]
Abstract
Osteoarthritis (OA) poses a significant global health challenge, with its prevalence anticipated to increase in the coming years. This review delves into the emerging molecular biomarkers in OA pathology, focusing on the roles of various molecules such as metabolites, noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Advances in omics technologies have transformed biomarker identification, enabling comprehensive analyses of the complex pathways involved in OA pathogenesis. Notably, ncRNAs, especially miRNAs and lncRNAs, exhibit dysregulated expression patterns in OA, presenting promising opportunities for diagnosis and therapy. Additionally, the intricate interplay between epigenetic modifications and OA progression highlights the regulatory role of epigenetics in gene expression dynamics. Genome-wide association studies have pinpointed key genes undergoing epigenetic changes, providing insights into the inflammatory processes and chondrocyte hypertrophy typical of OA. Understanding the molecular landscape of OA, including biomarkers and epigenetic mechanisms, holds significant potential for developing innovative diagnostic tools and therapeutic strategies for OA management.
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Affiliation(s)
- Mohammadreza Shakeri
- MD, Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Department of Orthopedic, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Aminian
- MD, Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Department of Orthopedic, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Khatere Mokhtari
- Department of Cellular and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Mohammadreza Bahaeddini
- MD, Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Department of Orthopedic, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Pouria Tabrizian
- MD, Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Department of Orthopedic, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Chen J, Zhang E, Wan Y, Huang T, Wang Y, Jiang H. A quick and innovative pipeline for producing chondrocyte-homing peptide-modified extracellular vesicles by three-dimensional dynamic culture of hADSCs spheroids to modulate the fate of remaining ear chondrocytes in the M1 macrophage-infiltrated microenvironment. J Nanobiotechnology 2024; 22:300. [PMID: 38816719 PMCID: PMC11141023 DOI: 10.1186/s12951-024-02567-5] [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: 01/28/2024] [Accepted: 05/16/2024] [Indexed: 06/01/2024] Open
Abstract
BACKGROUND Extracellular vesicles (EVs) derived from human adipose-derived mesenchymal stem cells (hADSCs) have shown great therapeutic potential in plastic and reconstructive surgery. However, the limited production and functional molecule loading of EVs hinder their clinical translation. Traditional two-dimensional culture of hADSCs results in stemness loss and cellular senescence, which is unfavorable for the production and functional molecule loading of EVs. Recent advances in regenerative medicine advocate for the use of three-dimensional culture of hADSCs to produce EVs, as it more accurately simulates their physiological state. Moreover, the successful application of EVs in tissue engineering relies on the targeted delivery of EVs to cells within biomaterial scaffolds. METHODS AND RESULTS The hADSCs spheroids and hADSCs gelatin methacrylate (GelMA) microspheres are utilized to produce three-dimensional cultured EVs, corresponding to hADSCs spheroids-EVs and hADSCs microspheres-EVs respectively. hADSCs spheroids-EVs demonstrate excellent production and functional molecule loading compared with hADSCs microspheres-EVs. The upregulation of eight miRNAs (i.e. hsa-miR-486-5p, hsa-miR-423-5p, hsa-miR-92a-3p, hsa-miR-122-5p, hsa-miR-223-3p, hsa-miR-320a, hsa-miR-126-3p, and hsa-miR-25-3p) and the downregulation of hsa-miR-146b-5p within hADSCs spheroids-EVs show the potential of improving the fate of remaining ear chondrocytes and promoting cartilage formation probably through integrated regulatory mechanisms. Additionally, a quick and innovative pipeline is developed for isolating chondrocyte homing peptide-modified EVs (CHP-EVs) from three-dimensional dynamic cultures of hADSCs spheroids. CHP-EVs are produced by genetically fusing a CHP at the N-terminus of the exosomal surface protein LAMP2B. The CHP + LAMP2B-transfected hADSCs spheroids were cultured with wave motion to promote the secretion of CHP-EVs. A harvesting method is used to enable the time-dependent collection of CHP-EVs. The pipeline is easy to set up and quick to use for the isolation of CHP-EVs. Compared with nontagged EVs, CHP-EVs penetrate the biomaterial scaffolds and specifically deliver the therapeutic miRNAs to the remaining ear chondrocytes. Functionally, CHP-EVs show a major effect on promoting cell proliferation, reducing cell apoptosis and enhancing cartilage formation in remaining ear chondrocytes in the M1 macrophage-infiltrated microenvironment. CONCLUSIONS In summary, an innovative pipeline is developed to obtain CHP-EVs from three-dimensional dynamic culture of hADSCs spheroids. This pipeline can be customized to increase EVs production and functional molecule loading, which meets the requirements for regulating remaining ear chondrocyte fate in the M1 macrophage-infiltrated microenvironment.
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Affiliation(s)
- Jianguo Chen
- Chinese Academy of Medical Sciences & Peking Union Medical College Plastic Surgery Hospital and Institute, Shijingshan District, Beijing, 100144, China
| | - Enchong Zhang
- Department of Urology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China.
| | - Yingying Wan
- DongFang Hospital of Beijing University of Chinese Medicine, Fengtai District, Beijing, 100078, China.
| | - Tianyu Huang
- Chinese Academy of Medical Sciences & Peking Union Medical College Plastic Surgery Hospital and Institute, Shijingshan District, Beijing, 100144, China
| | - Yuchen Wang
- Chinese Academy of Medical Sciences & Peking Union Medical College Plastic Surgery Hospital and Institute, Shijingshan District, Beijing, 100144, China
| | - Haiyue Jiang
- Chinese Academy of Medical Sciences & Peking Union Medical College Plastic Surgery Hospital and Institute, Shijingshan District, Beijing, 100144, China.
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Zhang Y, Liu H, Niu M, Wang Y, Xu R, Guo Y, Zhang C. Roles of long noncoding RNAs in human inflammatory diseases. Cell Death Discov 2024; 10:235. [PMID: 38750059 PMCID: PMC11096177 DOI: 10.1038/s41420-024-02002-6] [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: 07/06/2023] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 05/18/2024] Open
Abstract
Chemokines, cytokines, and inflammatory cells mediate the onset and progression of many diseases through the induction of an inflammatory response. LncRNAs have emerged as important regulators of gene expression and signaling pathways. Increasing evidence suggests that lncRNAs are key players in the inflammatory response, making it a potential therapeutic target for various diseases. From the perspective of lncRNAs and inflammatory factors, we summarized the expression level and regulatory mechanisms of lncRNAs in human inflammatory diseases, such as cardiovascular disease, osteoarthritis, sepsis, chronic obstructive pulmonary disease, asthma, acute lung injury, diabetic retinopathy, and Parkinson's disease. We also summarized the functions of lncRNAs in the macrophages polarization and discussed the potential applications of lncRNAs in human inflammatory diseases. Although our understanding of lncRNAs is still in its infancy, these data will provide a theoretical basis for the clinical application of lncRNAs.
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Affiliation(s)
- Yuliang Zhang
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
| | - Hongliang Liu
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Min Niu
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Ying Wang
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Rong Xu
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Yujia Guo
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Chunming Zhang
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
- Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, China.
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10
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Fu XP, Ji CY, Tang WQ, Yu TT, Luo L. Long non-coding RNA LOXL1-AS1: a potential biomarker and therapeutic target in human malignant tumors. Clin Exp Med 2024; 24:93. [PMID: 38693424 PMCID: PMC11062969 DOI: 10.1007/s10238-024-01355-7] [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: 03/26/2024] [Accepted: 04/15/2024] [Indexed: 05/03/2024]
Abstract
Long non-coding RNAs (lncRNAs) are transcripts that contain more than 200 nucleotides. Despite their inability to code proteins, multiple studies have identified their important role in human cancer through different mechanisms. LncRNA lysyl oxidase like 1 antisense RNA 1 (LOXL1-AS1), a newly discovered lncRNA located on human chromosome 15q24.1, has recently been shown to be involved in the occurrence and progression of various malignancies, such as colorectal cancer, gastric cancer, hepatocellular carcinoma, prostate cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, breast cancer, glioma, thymic carcinoma, pancreatic carcinoma. LOXL1-AS1 acts as competitive endogenous RNA (ceRNA) and via sponging various miRNAs, including miR-374b-5p, miR-21, miR-423-5p, miR-589-5p, miR-28-5p, miR-324-3p, miR-708-5p, miR-143-3p, miR-18b-5p, miR-761, miR-525-5p, miR-541-3p, miR-let-7a-5p, miR-3128, miR-3614-5p, miR-377-3p and miR-1224-5p to promote tumor cell proliferation, invasion, migration, apoptosis, cell cycle, and epithelial-mesenchymal transformation (EMT). In addition, LOXL1-AS1 is involved in the regulation of P13K/AKT and MAPK signaling pathways. This article reviews the current understanding of the biological function and clinical significance of LOXL1-AS1 in human cancers. These findings suggest that LOXL1-AS1 may be both a reliable biomarker and a potential therapeutic target for cancers.
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Affiliation(s)
- Xiao-Ping Fu
- Department of Health Management Center, Hubei Provincial Hospital of Traditional Chinese Medicine, Hongshan District, 856 Luoyu Road, Wuhan, 430070, People's Republic of China
| | - Chun-Yan Ji
- Department of Gastroenterology, Hubei Provincial Hospital of Traditional Chinese and Western Medicine, Wuhan, 430015, People's Republic of China
| | - Wen-Qian Tang
- Department of Health Management Center, Hubei Provincial Hospital of Traditional Chinese Medicine, Hongshan District, 856 Luoyu Road, Wuhan, 430070, People's Republic of China
| | - Ting-Ting Yu
- School of Clinical Medical, Hubei University of Chinese Medicine, Wuhan, 443000, People's Republic of China
| | - Lei Luo
- Department of Health Management Center, Hubei Provincial Hospital of Traditional Chinese Medicine, Hongshan District, 856 Luoyu Road, Wuhan, 430070, People's Republic of China.
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11
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Chen B, Lin C, Jin X, Zhang X, Yang K, Wang J, Zhang F, Zhang Y, Ji Y, Meng Z. Construction of a diagnostic model for osteoarthritis based on transcriptomic immune-related genes. Heliyon 2024; 10:e23636. [PMID: 38187306 PMCID: PMC10770511 DOI: 10.1016/j.heliyon.2023.e23636] [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: 08/11/2023] [Revised: 12/08/2023] [Accepted: 12/08/2023] [Indexed: 01/09/2024] Open
Abstract
BACKGROUND Osteoarthritis (OA) is a leading cause of disability globally, affecting over 500 million individuals worldwide. However, accurate and early diagnosis of OA is challenging to achieve. Immune-related genes play an essential role in OA development. Therefore, the objective of this study was to develop a diagnostic model for OA based on immune-related genes identified in synovial membrane. METHODS The gene expression profile of OA were downloaded based on four datasets. The significantly differentially expressed genes (DEGs) between OA and control groups were selected. The differential immune cells were analyzed, followed by immune-related DEGs screening. WGCNA was used to screen module genes and these genes were further selected through optimization algorithm. Then, nomogram model was constructed. Chemical drug small molecule related to OA was predicted. Finally, expression levels of several key genes were validated by qRT-PCR through construction of OA rat models. RESULTS The total 656 DEGs were obtained. Eight immune cells were significantly differential between two groups, and 317 immune-related DEGs were obtained. WGCNA identified three modules. The genes in modules were significantly involved in 15 pathways, involving in 65 genes. Then 12 DEGs were screened as the final optimal combination of DEGs, such as CEBPB, CXCL1, JUND, GABARAPL2 and PDGFC. The Nomogram model was also constructed. Furthermore, the chemical small molecules, such as acetaminophen, aspirin, and caffeine were predicted. The expression levels of CEBPB, CXCL1, GABARAPL2 and PDGFC were validated in OA rat models. CONCLUSION A diagnostic model based on twelve immune related genes was constructed. These model genes, such as CEBPB, CXCL1, GABARAPL2, and PDGFC, may serve as diagnostic biomarkers and immunotherapeutic targets.
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Affiliation(s)
- Bo Chen
- Rehabilitation Medicine Department, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225001, China
| | - Chun Lin
- Rehabilitation Medicine Department, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225001, China
| | - Xing Jin
- Rehabilitation Medicine Department, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225001, China
| | - Xibin Zhang
- Rehabilitation Medicine Department, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225001, China
| | - Kang Yang
- Rehabilitation Medicine Department, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225001, China
| | - Jianjian Wang
- Rehabilitation Medicine Department, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225001, China
| | - Feng Zhang
- Rehabilitation Medicine Department, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225001, China
| | - Yuxin Zhang
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
- Department of Rehabilitation Medicine, Huangpu Branch, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yingying Ji
- The affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, Jiangsu, 214151, China
| | - Zhaoxiang Meng
- Rehabilitation Medicine Department, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225001, China
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12
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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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13
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Zhou J, Huang J, Li Z, Song Q, Yang Z, Wang L, Meng Q. Identification of aging-related biomarkers and immune infiltration characteristics in osteoarthritis based on bioinformatics analysis and machine learning. Front Immunol 2023; 14:1168780. [PMID: 37503333 PMCID: PMC10368975 DOI: 10.3389/fimmu.2023.1168780] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 06/27/2023] [Indexed: 07/29/2023] Open
Abstract
Background Osteoarthritis (OA) is a degenerative disease closely related to aging. Nevertheless, the role and mechanisms of aging in osteoarthritis remain unclear. This study aims to identify potential aging-related biomarkers in OA and to explore the role and mechanisms of aging-related genes and the immune microenvironment in OA synovial tissue. Methods Normal and OA synovial gene expression profile microarrays were obtained from the Gene Expression Omnibus (GEO) database and aging-related genes (ARGs) from the Human Aging Genomic Resources database (HAGR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO), and Gene set variation analysis (GSVA) enrichment analysis were used to uncover the underlying mechanisms. To identify Hub ARDEGs with highly correlated OA features (Hub OA-ARDEGs), Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning methods were used. Furthermore, we created diagnostic nomograms and receiver operating characteristic curves (ROC) to assess Hub OA-ARDEGs' ability to diagnose OA and predict which miRNAs and TFs they might act on. The Single sample gene set enrichment analysis (ssGSEA) algorithm was applied to look at the immune infiltration characteristics of OA and their relationship with Hub OA-ARDEGs. Results We discovered 87 ARDEGs in normal and OA synovium samples. According to functional enrichment, ARDEGs are primarily associated with inflammatory regulation, cellular stress response, cell cycle regulation, and transcriptional regulation. Hub OA-ARDEGs with excellent OA diagnostic ability were identified as MCL1, SIK1, JUND, NFKBIA, and JUN. Wilcox test showed that Hub OA-ARDEGs were all significantly downregulated in OA and were validated in the validation set and by qRT-PCR. Using the ssGSEA algorithm, we discovered that 15 types of immune cell infiltration and six types of immune cell activation were significantly increased in OA synovial samples and well correlated with Hub OA-ARDEGs. Conclusion Synovial aging may promote the progression of OA by inducing immune inflammation. MCL1, SIK1, JUND, NFKBIA, and JUN can be used as novel diagnostic biomolecular markers and potential therapeutic targets for OA.
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Affiliation(s)
- JiangFei Zhou
- Department of Orthopedics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Jian Huang
- Department of Traumatic Orthopaedics, The Central Hospital of Xiaogan, Xiaogan, Hubei, China
| | - ZhiWu Li
- Department of Orthopedics, The 2nd People’s Hospital of Bijie, Bijie, Guizhou, China
| | - QiHe Song
- Department of Traumatic Orthopaedics, The Central Hospital of Xiaogan, Xiaogan, Hubei, China
| | - ZhenYu Yang
- Department of Orthopedics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Lu Wang
- Department of Neurology, The Central Hospital of Xiaogan, Xiaogan, Hubei, China
| | - QingQi Meng
- Department of Orthopedics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
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14
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Wang P, Wang Y, Ma B. Long noncoding RNA NAV2-AS5 relieves chondrocyte inflammation by targeting miR-8082/ TNIP2 in osteoarthritis. Cell Cycle 2023; 22:796-807. [PMID: 36503346 PMCID: PMC10026897 DOI: 10.1080/15384101.2022.2154554] [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] [Indexed: 12/14/2022] Open
Abstract
Osteoarthritis (OA) is a common chronic and frequently occurring orthopedic disease in the middle-aged and elderly individuals. Numerous studies have shown that long noncoding RNAs (lncRNAs) play major roles in various diseases. However, the potential molecular mechanism of action of NAV2-AS5 in OA remains unclear. The present study was designed to explore the influence of NAV2-AS5 on the progression of chondrocyte inflammation and its underlying molecular mechanisms. To simulate the inflammatory environment in OA, the human chondrocyte cell line was treated with LPS. Cell proliferation, cell cycle progression, and apoptosis were assessed using Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine analysis, and flow cytometry. Proliferation- and cycle-related proteins and the release of inflammatory factors were examined by western blot analysis and enzyme-linked immunosorbent assay. The downstream targets of NAV2-AS5 were determined using bioinformatics and confirmed by a luciferase reporter assay. In our study, patients with OA showed downregulation of NAV2-AS5, upregulation of miR-8082, and downregulation of TNFAIP3 interacting protein 2 (TNIP2). Moreover, we found that both overexpression of NAV2-AS5 and miR-8082 inhibitor promoted cell proliferation, inhibited apoptosis, and released inflammatory cytokines in LPS-treated chondrocytes. MiR-8082 was predicted to be a target of both NAV2-AS5 and TNIP2. In addition, rescue experiments showed that silencing of TNIP2 reversed the effects of the miR-8082 inhibitor on proliferation, cell cycle, apoptosis, and inflammatory factors in sh-NAV2-AS5-treated chondrocytes. In conclusion, these findings indicate that NAV2-AS5 relieves chondrocyte inflammation by targeting miR-8082/TNIP2 in OA, which provides a new theoretical basis for OA therapy.
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Affiliation(s)
- Pu Wang
- Department of Orthopedics, The Second Affiliated Hospital of The Air Force Medical University (Tangdu Hospital of Fourth Military Medical University), Xi'an, Shaanxi, P.R. China
| | - Yuhao Wang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi 'an, Shaanxi, P.R.China
| | - Baoan Ma
- Department of Orthopedics, The Second Affiliated Hospital of The Air Force Medical University (Tangdu Hospital of Fourth Military Medical University), Xi'an, Shaanxi, P.R. China
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15
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Assi R, Cherifi C, Cornelis FMF, Zhou Q, Storms L, Pazmino S, Coutinho de Almeida R, Meulenbelt I, Lories RJ, Monteagudo S. Inhibition of KDM7A/B histone demethylases restores H3K79 methylation and protects against osteoarthritis. Ann Rheum Dis 2023:ard-2022-223789. [PMID: 36927643 DOI: 10.1136/ard-2022-223789] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/07/2023] [Indexed: 03/18/2023]
Abstract
OBJECTIVES In osteoarthritis, methylation of lysine 79 on histone H3 (H3K79me), a protective epigenetic mechanism, is reduced. Histone methylation levels are dynamically regulated by histone methyltransferases and demethylases. Here, we aimed to identify which histone demethylases regulate H3K79me in cartilage and investigate whether their targeting protects against osteoarthritis. METHODS We determined histone demethylase expression in human non-osteoarthritis and osteoarthritis cartilage using qPCR. The role of histone demethylase families and subfamilies on H3K79me was interrogated by treatment of human C28/I2 chondrocytes with pharmacological inhibitors, followed by western blot and immunofluorescence. We performed C28/I2 micromasses to evaluate effects on glycosaminoglycans by Alcian blue staining. Changes in H3K79me after destabilisation of the medial meniscus (DMM) in mice were determined by immunohistochemistry. Daminozide, a KDM2/7 subfamily inhibitor, was intra-articularly injected in mice upon DMM. Histone demethylases targeted by daminozide were individually silenced in chondrocytes to dissect their role on H3K79me and osteoarthritis. RESULTS We documented the expression signature of histone demethylases in human non-osteoarthritis and osteoarthritis articular cartilage. Inhibition of Jumonji-C demethylase family increased H3K79me in human chondrocytes. Blockade of KDM2/7 histone demethylases with daminozide increased H3K79me and glycosaminoglycans. In mouse articular cartilage, H3K79me decayed rapidly upon induction of joint injury. Early and sustained intra-articular treatment with daminozide enhanced H3K79me and exerted protective effects in mice upon DMM. Individual silencing of KDM7A/B demethylases in human chondrocytes demonstrated that KDM7A/B mediate protective effects of daminozide on H3K79me and osteoarthritis. CONCLUSION Targeting KDM7A/B histone demethylases could be an attractive strategy to protect joints against osteoarthritis.
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Affiliation(s)
- Reem Assi
- Development and Regeneration, Skeletal Biology and Engineering Research Center, Laboratory of Tissue Homeostasis and Disease, KU Leuven, Leuven, Belgium
| | - Chahrazad Cherifi
- Development and Regeneration, Skeletal Biology and Engineering Research Center, Laboratory of Tissue Homeostasis and Disease, KU Leuven, Leuven, Belgium .,Glycobiology Cell Growth Tissue Repair and Regeneration Research Unit, Gly-CRRET, Univ Paris Est Créteil, Créteil, France
| | - Frederique M F Cornelis
- Development and Regeneration, Skeletal Biology and Engineering Research Center, Laboratory of Tissue Homeostasis and Disease, KU Leuven, Leuven, Belgium
| | - Qiongfei Zhou
- Development and Regeneration, Skeletal Biology and Engineering Research Center, Laboratory of Tissue Homeostasis and Disease, KU Leuven, Leuven, Belgium
| | - Lies Storms
- Development and Regeneration, Skeletal Biology and Engineering Research Center, Laboratory of Tissue Homeostasis and Disease, KU Leuven, Leuven, Belgium
| | - Sofia Pazmino
- Development and Regeneration, Skeletal Biology and Engineering Research Centre, KU Leuven, Leuven, Belgium
| | - Rodrigo Coutinho de Almeida
- Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ingrid Meulenbelt
- Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.,Integrated research on Developmental determinants of Ageing and Longevity (IDEAL), Leiden University Medical Center, Leiden, The Netherlands
| | - Rik J Lories
- Development and Regeneration, Skeletal Biology and Engineering Research Center, Laboratory of Tissue Homeostasis and Disease, KU Leuven, Leuven, Belgium.,Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium
| | - Silvia Monteagudo
- Development and Regeneration, Skeletal Biology and Engineering Research Center, Laboratory of Tissue Homeostasis and Disease, KU Leuven, Leuven, Belgium
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16
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Huang L, Xiong S, Liu H, Li M, Zhang R, Liu Y, Hu X. Bioinformatics Analysis of the Inflammation-Associated lncRNA-mRNA Coexpression Network in Type 2 Diabetes. J Renin Angiotensin Aldosterone Syst 2023; 2023:6072438. [PMID: 36874406 PMCID: PMC9977555 DOI: 10.1155/2023/6072438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 01/31/2023] [Indexed: 02/25/2023] Open
Abstract
Introduction Diabetes is a chronic inflammatory state, and a key role of lncRNAs in diabetes complications is a new area of research. Methods In this study, key lncRNAs related to diabetes inflammation were identified by RNA-chip mining and lncRNA-mRNA coexpression network construction and finally verified by RT-qPCR. Results We ultimately obtained 12 genes, including A1BG-AS1, AC084125.4, RAMP2-AS1, FTX, DBH-AS1, LOXL1-AS1, LINC00893, LINC00894, PVT1, RUSC1-AS1, HCG25, and ATP1B3-AS1. RT-qPCR assays verified that LOXL1-AS1, A1BG-AS1, FTX, PVT1, and HCG25 were upregulated in the HG+LPS-induced THP-1 cells, and LINC00893, LINC00894, RUSC1-AS1, DBH-AS1, and RAMP2-AS1 were downregulated in the HG+LPS-induced THP-1 cells. Conclusions lncRNAs and mRNAs are extensively linked and form a coexpression network, and lncRNAs may influence the development of type 2 diabetes by regulating the corresponding mRNAs. The ten key genes obtained may become biomarkers of inflammation in type 2 diabetes in the future.
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Affiliation(s)
- Linjuan Huang
- The Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Shengxi Xiong
- The Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Hanshuang Liu
- The Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Min Li
- The Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Ranran Zhang
- The Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Yan Liu
- The Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Xiaolei Hu
- The Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
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17
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Song B, Dang H, Dong R. Differential Expression of LOXL1-AS1 in Coronary Heart Disease and its Regulatory Mechanism in ox-LDL-Induced Human Coronary Artery Endothelial Cell Pyroptosis. Cardiovasc Drugs Ther 2023; 37:75-87. [PMID: 34633594 DOI: 10.1007/s10557-021-07274-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/29/2021] [Indexed: 01/14/2023]
Abstract
OBJECTIVE Coronary heart disease (CHD) is a notable contributor to the burden of human health. Dysregulated long non-coding RNAs (lncRNAs) are implicated in the pathogenesis of CHD. This study investigated the expression pattern of lncRNA LOXL1-AS1 in CHD and its regulatory mechanism in oxidized low-density lipoprotein (ox-LDL)-induced human coronary artery endothelial cell (HCAEC) pyroptosis. METHODS Serum was collected from 62 CHD patients and 62 healthy volunteers for the detection of LOXL1-AS1 expression. The value of LOXL1-AS1 in CHD diagnosis and major cardiovascular adverse event (MACE) prediction was analyzed using the ROC curve. LOXL1-AS1, miR-16-5p, and SNX16 expressions in ox-LDL-treated HCAECs were determined using RT-qPCR. NLPR3, cleaved-caspase-1, and GSDMD-N protein levels were measured using Western blot. IL-1β and IL-18 concentrations were measured using ELISA. The binding relationships between LOXL1-AS1 and miR-16-5p and miR-16-5p and SNX16 were verified. Functional rescue experiment was performed to verify the role of miR-16-5p in HCAEC pyroptosis. RESULTS LOXL1-AS1 was highly expressed in CHD patients. LOXL1-AS1 had diagnostic value for CHD and predictive value for MACE occurrence. ox-LDL-treated HCAECs showed reduced viability, increased IL-1β and IL-18 concentrations, and elevated NLPR3, cleaved-caspase-1, and GSDMD-N levels. LOXL1-AS1 silencing promoted cell viability and reduced pyroptosis. LOXL1-AS1 bound to miR-16-5p and miR-16-5p targeted SNX16. Inhibition of miR-16-5p reversed the inhibitory effect of LOXL1-AS1 silencing on HCAEC pyroptosis. CONCLUSION LOXL1-AS1 was elevated in CHD patients with a good diagnostic value for CHD and predictive value for MACE. LOXL1-AS1 downregulated miR-16-5p expression by binding to miR-16-5p to enhance ox-LDL-induced HCAEC pyroptosis, which may be associated with upregulation of SNX16 transcription.
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Affiliation(s)
- Bangrong Song
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Anzhen Road, Chaoyang, Beijing, 100029, People's Republic of China
| | - Haiming Dang
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Anzhen Road, Chaoyang, Beijing, 100029, People's Republic of China
| | - Ran Dong
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Anzhen Road, Chaoyang, Beijing, 100029, People's Republic of China.
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18
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Gu J, Rao W, Huo S, Fan T, Qiu M, Zhu H, Chen D, Sheng X. MicroRNAs and long non-coding RNAs in cartilage homeostasis and osteoarthritis. Front Cell Dev Biol 2022; 10:1092776. [PMID: 36582467 PMCID: PMC9793335 DOI: 10.3389/fcell.2022.1092776] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022] Open
Abstract
During the last decade, osteoarthritis (OA) has become one of the most prevalent musculoskeletal diseases worldwide. OA is characterized by progressive loss of articular cartilage, abnormal remodeling of subchondral bone, hyperplasia of synovial cells, and growth of osteophytes, which lead to chronic pain and disability. The pathological mechanisms underlying OA initiation and progression are still poorly understood. Non-coding RNAs (ncRNAs) constitute a large portion of the transcriptome that do not encode proteins but function in numerous biological processes. Cumulating evidence has revealed a strong association between the changes in expression levels of ncRNA and the disease progression of OA. Moreover, loss- and gain-of-function studies utilizing transgenic animal models have demonstrated that ncRNAs exert vital functions in regulating cartilage homeostasis, degeneration, and regeneration, and changes in ncRNA expression can promote or decelerate the progression of OA through distinct molecular mechanisms. Recent studies highlighted the potential of ncRNAs to serve as diagnostic biomarkers, prognostic indicators, and therapeutic targets for OA. MiRNAs and lncRNAs are two major classes of ncRNAs that have been the most widely studied in cartilage tissues. In this review, we focused on miRNAs and lncRNAs and provided a comprehensive understanding of their functional roles as well as molecular mechanisms in cartilage homeostasis and OA pathogenesis.
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Affiliation(s)
- Jingliang Gu
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wu Rao
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shaochuan Huo
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Tianyou Fan
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Minlei Qiu
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haixia Zhu
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Deta Chen
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoping Sheng
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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19
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Wang R, Shiu HT, Lee WYW. Emerging role of lncRNAs in osteoarthritis: An updated review. Front Immunol 2022; 13:982773. [PMID: 36304464 PMCID: PMC9593085 DOI: 10.3389/fimmu.2022.982773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Osteoarthritis (OA) is a prevalent joint disease, which is associated with progressive articular cartilage loss, synovial inflammation, subchondral sclerosis and meniscus injury. The molecular mechanism underlying OA pathogenesis is multifactorial. Long non-coding RNAs (lncRNAs) are non-protein coding RNAs with length more than 200 nucleotides. They have various functions such as modulating transcription and protein activity, as well as forming endogenous small interfering RNAs (siRNAs) and microRNA (miRNA) sponges. Emerging evidence suggests that lncRNAs might be involved in the pathogenesis of OA which opens up a new avenue for the development of new biomarkers and therapeutic strategies. The purpose of this review is to summarize the current clinical and basic experiments related to lncRNAs and OA with a focus on the extensively studied H19, GAS5, MALAT1, XIST and HOTAIR. The potential translational value of these lncRNAs as therapeutic targets for OA is also discussed.
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Affiliation(s)
- Rongliang Wang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Hong Kong, China
| | - Hoi Ting Shiu
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Wayne Yuk Wai Lee
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Hong Kong, China
- *Correspondence: Wayne Yuk Wai Lee,
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20
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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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21
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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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22
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Quintero D, Rodriguez HC, Potty AG, Kouroupis D, Gupta A. Long noncoding RNAs in mesenchymal stromal/stem cells osteogenic differentiation: Implications in osteoarthritis pathogenesis. World J Stem Cells 2022; 14:429-434. [PMID: 35949395 PMCID: PMC9244951 DOI: 10.4252/wjsc.v14.i6.429] [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: 03/26/2022] [Revised: 04/27/2022] [Accepted: 05/21/2022] [Indexed: 02/06/2023] Open
Abstract
This letter focuses on a recently published article that provided an exceptional description of the effect of epigenetic modifications on gene expression patterns related to skeletal system remodeling. Specifically, it discusses a novel modality of epigenetic regulation, the long noncoding RNAs (lncRNAs), and provides evidence of their involvement in mesenchymal stromal/stem cells osteo-/adipo-genic differentiation balance. Despite focus on lncRNAs, there is an emerging cross talk between lncRNAs and miRNAs interaction as a novel mechanism in the regulation of the function of the musculoskeletal system, by controlling bone homeostasis and bone regeneration, as well as the osteogenic differentiation of stem cells. Thus, we touched on some examples to demonstrate this interaction. In addition, we believe there is still much to discover from the effects of lncRNAs on progenitor and non-progenitor cell differentiation. We incorporated data from other published articles to review lncRNAs in normal progenitor cell osteogenic differentiation, determined lncRNAs involved in osteoarthritis pathogenesis in progenitor cells, and provided a review of lncRNAs in non-progenitor cells that are differentially regulated in osteoarthritis. In conclusion, we really enjoyed reading this article and with this information we hope to further our under standing of lncRNAs and mesenchymal stromal/stem cells regulation.
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Affiliation(s)
- Daniel Quintero
- Department of Orthopaedics, Division of Sports Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
| | - Hugo C Rodriguez
- Holy Cross Orthopedic Institute: Fort Lauderdale Practice, Oakland Park, FL 33334, United States
| | - Anish G Potty
- South Texas Orthopedic Research Institute, Laredo, TX 78045 United States
| | - Dimitrios Kouroupis
- Diabetes Research Institute, Cell Transplant Center, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
| | - Ashim Gupta
- South Texas Orthopedic Research Institute, Laredo, TX 78045 United States
- BioIntegrate, Lawrenceville, GA 30043, United States
- Future Biologics, Lawrenceville, GA 30043, United States.
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23
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Chen P, Tang S, Gao H, Zhang H, Chen C, Fang Z, Peng G, Weng H, Chen A, Zhang C, Qiu Z, Li S, Chen J, Chen L, Chen X. Wharton's jelly mesenchymal stem cell-derived small extracellular vesicles as natural nanoparticles to attenuate cartilage injury via microRNA regulation. Int J Pharm 2022; 623:121952. [PMID: 35753534 DOI: 10.1016/j.ijpharm.2022.121952] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 10/17/2022]
Abstract
The main strategy of tissue repair and regeneration focuses on the application of mesenchymal stem cells and cell-based nanoparticles, but there are still multiple challenges that may have negative impacts on human safety and therapeutic efficacy. Cell-free nanotechnology can effectively overcome these obstacles and limitations. Mesenchymal stem cell (MSC)-derived natural small extracellular vesicles (sEVs) represent ideal nanotherapeutics due to their low immunogenicity and lack of tumorigenicity. Here, sEVs harvested from Wharton's jelly mesenchymal stem cells (WJMSCs) were identified. In vitro results showed that WJMSC-sEVs efficiently entered chondrocytes in the osteoarthritis (OA) model, further promoted chondrocyte migration and proliferation and modulated immune reactivity. In vivo, WJMSC-sEVs notably promoted chondrogenesis, which was consistent with the effect of WJMSCs. RNA sequencing results revealed that sEV-microRNA-regulated biocircuits can significantly contribute to the treatment of OA, such as by promoting the activation of the calcium signaling pathway, ECM-receptor interaction pathway and NOTCH signaling pathway. In particular, let-7e-5p, which is found in WJMSC-sEVs, was shown to be a potential core molecule for promoting cartilage regeneration by regulating the levels of STAT3 and IGF1R. Our findings suggest that WJMSC-sEV-induced chondrogenesis is a promising innovative and feasible cell-free nanotherapy for OA treatment.
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Affiliation(s)
- Penghong Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Shijie Tang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Hangqi Gao
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Haoruo Zhang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Caixiang Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Zhuoqun Fang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Guohao Peng
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Haiyan Weng
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Aizhen Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Chaoyu Zhang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Zhihuang Qiu
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Shirong Li
- Department of Plastic and Reconstructive Surgery, Shinrong Plastic Surgery Hospital, Chongqing, China
| | - Jinghua Chen
- Department of Pharmaceutical Analysis, the School of Pharmacy, Fujian Medical University, Fuzhou, 350100, China.
| | - Liangwan Chen
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
| | - Xiaosong Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China.
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24
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Zhang L, Fu Z, Huang Y, Luo W. LOXL1-AS1 alleviates inflammatory response in the epicardial adipose tissue with coronary artery disease by sponging miR-3614. Int J Cardiol 2022; 359:113. [DOI: 10.1016/j.ijcard.2022.03.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/08/2022] [Indexed: 11/26/2022]
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25
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Zhang Y, Zheng H, Li B. Circ_0110251 overexpression alleviates IL-1β-induced chondrocyte apoptosis and extracellular matrix degradation by regulating miR-3189-3p/SPRY1 axis in osteoarthritis. Autoimmunity 2022; 55:168-178. [PMID: 35196925 DOI: 10.1080/08916934.2022.2027917] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Mounting evidence indicates that circular RNAs (circRNAs) are involved in the progression of human diseases, including osteoarthritis (OA). In this study, we focussed on the functions and potential mechanism of circ_0110251 in OA. METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine the expression of circ_0110251, collagen type XI alpha 1 chain (COL11A1), microRNA-3189-3p (miR-3189-3p) and sprouty receptor tyrosine kinase signalling antagonist 1 (SPRY1). The cyclisation analysis of circ_0110251 was analysed by RNase R and Actinomycin D assays. Flow cytometry analysis was conducted to analyse cell apoptosis. Western blot assay was used to measure the levels of extracellular matrix degradation (ECM)-associated markers and SPRY1. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay were performed to analyse the relationships among circ_0110251, miR-3189-3p and SPRY1. RESULTS Circ_0110251 was downregulated in OA cartilage tissues and IL-1β-induced chondrocytes. IL-1β promoted the apoptosis and ECM degradation in chondrocytes, while circ_0110251 overexpression relieved the effects. Circ_0110251 functioned as the sponge for miR-3189-3p and miR-3189-3p overexpression reversed the effect of circ_0110251 on IL-1β-induced chondrocyte damage. Additionally, SPRY1 served as the target gene of miR-3189-3p. MiR-3189-3p inhibition ameliorated IL-1β-induced chondrocyte apoptosis and ECM degradation, while SPRY1 silencing rescued the impacts. CONCLUSION Circ_0110251 protected chondrocytes from IL-1β-induced apoptosis and ECM degradation in OA via sponging miR-3189-3p and elevating SPRY1.
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Affiliation(s)
- Yawei Zhang
- Department of Emergency Orthopedics, Gansu Provincial Hospital of TCM, Lanzhou, China
| | - Hengheng Zheng
- Department of Emergency Orthopedics, Gansu Provincial Hospital of TCM, Lanzhou, China
| | - Baitong Li
- Department of Emergency Orthopedics, Gansu Provincial Hospital of TCM, Lanzhou, China
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26
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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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27
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Kong X, Chen R, Zhang L, Wu M, Wu J, Wei Y, Dai W, Jiang Y. ESR2 regulates PINK1-mediated mitophagy via transcriptional repression of microRNA-423 expression to promote asthma development. Pharmacol Res 2021; 174:105956. [PMID: 34700017 DOI: 10.1016/j.phrs.2021.105956] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 10/12/2021] [Accepted: 10/19/2021] [Indexed: 10/20/2022]
Abstract
Asthma represents an inflammatory airway disease related to the induction of airway eosinophilia, mucus overproduction, and bronchial hyperresponsiveness. This study explored the effects of microRNA-423 (miR-423) on mitophagy and inflammation in asthmatic mice challenged with house dust mites (HDMs) and rhinovirus (RV). By searching for differentially expressed miRNAs in the GSE25230 microarray, miR-423 was identified as our target. Moreover, miR-423 was expressed at low levels in the lung tissues from patients with asthma, and agomiR-423 significantly inhibited RV-induced inflammatory injury and activation of inflammasome signaling in mouse lung tissues. Additionally, miR-423 downregulated the expression of IL-1β/NLRP3/Caspase-1 inflammasome signaling by targeting phosphatase and tensin homolog-induced putative kinase 1 (PINK1). Furthermore, luciferase reporter experiments and ChIP-qPCR assays revealed that estrogen receptor 2 (ESR2) transcriptionally repressed miR-423 expression by coordinating with H3K9me2 modification of the miR-423 promoter histone. Overall, ESR2 synergized with the H3K9me2 modification of the miR-423 promoter histone to transcriptionally repress miR-423 expression and increase PINK1 expression in lung tissues, resulting in asthma exacerbation.
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Affiliation(s)
- Xiaomei Kong
- Department of Respiratory and Critical Care Medicine, the First Hospital of Shanxi Medical, University, Taiyuan 030002, Shanxi, PR China.
| | - Ru Chen
- Department of Respiratory and Critical Care Medicine, the First Hospital of Shanxi Medical, University, Taiyuan 030002, Shanxi, PR China
| | - Lina Zhang
- Intensive Care Unit, Liaocheng People's Hospital, Liaocheng 252000, Shandong, PR China
| | - Meiqiong Wu
- School of Public Health, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Juan Wu
- Department of Respiratory and Critical Care Medicine, the First Hospital of Shanxi Medical, University, Taiyuan 030002, Shanxi, PR China
| | - Yangyang Wei
- Department of Respiratory and Critical Care Medicine, the First Hospital of Shanxi Medical, University, Taiyuan 030002, Shanxi, PR China
| | - Wenjuan Dai
- Department of Respiratory and Critical Care Medicine, the First Hospital of Shanxi Medical, University, Taiyuan 030002, Shanxi, PR China
| | - Yi Jiang
- Department of Respiratory and Critical Care Medicine, the First Hospital of Shanxi Medical, University, Taiyuan 030002, Shanxi, PR China
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28
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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: 28] [Impact Index Per Article: 7.0] [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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29
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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: 134] [Impact Index Per Article: 33.5] [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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30
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Huang H, Xing D, Zhang Q, Li H, Lin J, He Z, Lin J. LncRNAs as a new regulator of chronic musculoskeletal disorder. Cell Prolif 2021; 54:e13113. [PMID: 34498342 PMCID: PMC8488571 DOI: 10.1111/cpr.13113] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 06/15/2021] [Accepted: 07/30/2021] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVES In recent years, long non-coding RNAs (lncRNAs) have been found to play a role in the occurrence, progression and prognosis of chronic musculoskeletal disorders. DESIGN AND METHODS Literature exploring on PubMed was conducted using the combination of keywords 'LncRNA' and each of the following: 'osteoarthritis', 'rheumatoid arthritis', 'osteoporosis', 'osteogenesis', 'osteoclastogenesis', 'gout arthritis', 'Kashin-Beck disease', 'ankylosing spondylitis', 'cervical spondylotic myelopathy', 'intervertebral disc degeneration', 'human muscle disease' and 'muscle hypertrophy and atrophy'. For each disorder, we focused on the publications in the last five years (5/1/2016-2021/5/1, except for Kashin-Beck disease). Finally, we excluded publications that had been reported in reviews of various musculoskeletal disorders during the last three years. Here, we summarized the progress of research on the role of lncRNA in multiple pathological processes during musculoskeletal disorders. RESULTS LncRNAs play a crucial role in regulating downstream gene expression and maintaining function and homeostasis of cells, especially in chondrocytes, synovial cells, osteoblasts, osteoclasts and skeletal muscle cells. CONCLUSIONS Understanding the mechanisms of lncRNAs in musculoskeletal disorders may provide promising strategies for clinical practice.
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Affiliation(s)
- Hesuyuan Huang
- Arthritis Clinic & Research CenterPeking University People's Hospital, Peking UniversityBeijingChina
- Arthritis InstitutePeking UniversityBeijingChina
| | - Dan Xing
- Arthritis Clinic & Research CenterPeking University People's Hospital, Peking UniversityBeijingChina
- Arthritis InstitutePeking UniversityBeijingChina
| | - Qingxi Zhang
- Arthritis Clinic & Research CenterPeking University People's Hospital, Peking UniversityBeijingChina
- Arthritis InstitutePeking UniversityBeijingChina
| | - Hui Li
- Arthritis Clinic & Research CenterPeking University People's Hospital, Peking UniversityBeijingChina
- Arthritis InstitutePeking UniversityBeijingChina
| | - Jianjing Lin
- Arthritis Clinic & Research CenterPeking University People's Hospital, Peking UniversityBeijingChina
- Arthritis InstitutePeking UniversityBeijingChina
| | - Zihao He
- Arthritis Clinic & Research CenterPeking University People's Hospital, Peking UniversityBeijingChina
- Arthritis InstitutePeking UniversityBeijingChina
| | - Jianhao Lin
- Arthritis Clinic & Research CenterPeking University People's Hospital, Peking UniversityBeijingChina
- Arthritis InstitutePeking UniversityBeijingChina
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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: 5] [Impact Index Per Article: 1.3] [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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Abstract
Osteoarthritis (OA), one of the most common motor system disorders, is a degenerative disease involving progressive joint destruction caused by a variety of factors. At present, OA has become the fourth most common cause of disability in the world. However, the pathogenesis of OA is complex and has not yet been clarified. Long non-coding RNA (lncRNA) refers to a group of RNAs more than 200 nucleotides in length with limited protein-coding potential, which have a wide range of biological functions including regulating transcriptional patterns and protein activity, as well as binding to form endogenous small interference RNAs (siRNAs) and natural microRNA (miRNA) molecular sponges. In recent years, a large number of lncRNAs have been found to be differentially expressed in a variety of pathological processes of OA, including extracellular matrix (ECM) degradation, synovial inflammation, chondrocyte apoptosis, and angiogenesis. Obviously, lncRNAs play important roles in regulating gene expression, maintaining the phenotype of cartilage and synovial cells, and the stability of the intra-articular environment. This article reviews the results of the latest research into the role of lncRNAs in a variety of pathological processes of OA, in order to provide a new direction for the study of OA pathogenesis and a new target for prevention and treatment. Cite this article: Bone Joint Res 2021;10(2):122-133.
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Affiliation(s)
- Chao Peng He
- Department of Orthopedics, The Second Affiliated Hospital, Hunan Normal University, Hunan, China
| | - Xin Chen Jiang
- Department of Orthopedics, The Second Affiliated Hospital, Hunan Normal University, Hunan, China
| | - Cheng Chen
- Department of Orthopedics, The Second Affiliated Hospital, Hunan Normal University, Hunan, China
| | - Hai Bin Zhang
- Department of Orthopedics, The Xiangya Hospital of Central South University Changsha, Hunan, China
| | - Wen Dong Cao
- Department of Orthopedics, The Second Affiliated Hospital, Hunan Normal University, Hunan, China
| | - Qi Wu
- Department of Orthopedics, The Second Affiliated Hospital, Hunan Normal University, Hunan, China
| | - Chi Ma
- Department of Orthopedics, The First Affiliated Hospital (People’s Hospital of Xiangxi Autonomous Prefecture), Jishou University, Jishou, China
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Wang B, Li J, Tian F. Downregulation of lncRNA SNHG14 attenuates osteoarthritis by inhibiting FSTL-1 mediated NLRP3 and TLR4/NF-κB pathway through miR-124-3p. Life Sci 2021; 270:119143. [PMID: 33539913 DOI: 10.1016/j.lfs.2021.119143] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 01/12/2021] [Accepted: 01/27/2021] [Indexed: 12/28/2022]
Abstract
Osteoarthritis (OA) is the joint pain and dysfunction syndrome caused by severe joint degeneration. The overproduced inflammatory mediators contribute greatly to OA development. It is reported that long non-coding RNA (lncRNA) takes part in many inflammatory diseases. Here, we mainly explored the function of lncRNA SNHG14 in OA process and its specific mechanisms. An OA rat model was induced by destabilizing the medial meniscus (DMM) and IL-1β (5 ng/mL) was used to mediate an OA cell model in particular chondrocytes (AC). Gain- or loss-of functional assays of SNHG14 and miR-124-3p were carried out to explore their roles in OA development. The experimental statistics illustrated that lncRNA SNHG14 and IL-1β mRNA expression were both increased in OA tissues, while miR-124-3p was lowly-expressed. Linear regression analysis showed that SNHG14 and miR-124-3p had negative relationship in the OA tissues. In the in vitro experiments, downregulation of lncRNA SNHG14 promoted the proliferation of IL-1β-treated AC and inhibited cell apoptosis and COX-2, iNOS, TNF-α, IL-6 expression. Moreover, lncRNA SNHG14 inhibited miR-124-3p expression as a miRNA sponge. MiR-124-3p targeted the 3'non-translated region (3'UTR) of FSTL-1 and TLR4 and inhibited their expressions. Also, the in vivo experiments confirmed that knocking down SNHG14 relieved the progression of OA in rats via inhibiting inflammatory responses. In conclusion, this study confirmed that downregulation of lncRNA SNHG14 inhibits FSTL-1-mediated activation of NLRP3 and TLR4/NF-κB signalling pathway activation by targeting miR-124-3p, thus attenuating inflammatory reactions in OA.
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Affiliation(s)
- Bin Wang
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning, China
| | - Jingyu Li
- Ultrasonic Department, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning, China.
| | - Feng Tian
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning, China
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Characterization of exosomal long non-coding RNAs in chondrogenic differentiation of human adipose-derived stem cells. Mol Cell Biochem 2021; 476:1411-1420. [PMID: 33389494 DOI: 10.1007/s11010-020-04003-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 11/24/2020] [Indexed: 12/16/2022]
Abstract
The exosomes derived from chondrogenic stem cells and long non-coding RNAs (lncRNAs) play a key role in cartilage regeneration. Here, we investigated the expression profile of exosomal lncRNAs in chondrogenesis of human adipose derived stem cells (hADSCs). hADSCs were induced to differentiate into chondrocytes in vitro. Exosomes from undifferentiated hADSCs and chondrogenic hADSCs were isolated. LncRNA and mRNA expression profiles in the isolated exosomes were analyzed by RNA sequencing. The resultant data were subjected to gene ontology (GO) terms and KEGG pathway analysis to identify differentially expressed lncRNAs. We identified 23 upregulated and 163 downregulated lncRNAs in exosomes derived from chondrogenic hADSCs compared to that in exosomes from undifferentiated hADSCs. In addition, analysis of mRNA expression data revealed 968 upregulated genes and 572 downregulated genes in exosomes of chondrogenic hADSCs. Lncrna and mRNA expression levels were further validated by qRT-PCR. Differentially expressed lncRNAs and mRNAs were utilized to construct a coding-non-coding gene co-expression network (CNC network). GO terms and KEGG pathway enrichment analysis revealed several significant processes differentially regulated between undifferentiated hADSCs and chondrogenic hADSCs. Taken together, this study revealed the differential expression of exosomal lncRNAs of chondrogenic hADSCs and provided a foundation for future study on the cartilage recovery mechanism of exosomes derived from chondrogenic stem cells.
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Suppression of lncRNA MALAT1 reduces pro-inflammatory cytokines production by regulating miR-150-5p/ZBTB4 axis through JAK/STAT signal pathway in systemic juvenile idiopathic arthritis. Cytokine 2020; 138:155397. [PMID: 33341002 DOI: 10.1016/j.cyto.2020.155397] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 12/03/2020] [Accepted: 12/03/2020] [Indexed: 12/13/2022]
Abstract
Systemic juvenile idiopathic arthritis (sJIA) is a common chronic disease occurring in children. Increasing studies have demonstrated that long noncoding RNAs (lncRNAs) play important roles in the pathogenesis of diverse human diseases. This study aimed to explore the role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and its mechanism in sJIA. We found that the expression of MALAT1, the plasma level of pro-inflammatory cytokines (IL-6, IL-17, IL-1β, and TNF-α) as well as MMP-8 and MMP-9 production were significantly elevated in sJIA patients. Moreover, we observed that the production of these cytokines in peripheral blood mononuclear cells (PBMCs) from sJIA patients were reduced after MALAT1 knockdown. Furthermore, bioinformatics analysis predicted that MALAT1 might bind to miR-150-5p and ZBTB4 was a downstream target gene of miR-150-5p. Besides, rescue assays revealed that MALAT1 knockdown-mediated suppressive effects on cytokine production could be reversed by ZBTB4 overexpression. In addition, MALAT1 activated the JAK/STAT signaling by upregulating ZBTB4 expression. In summary, our findings demonstrated that MALAT1 promoted pro-inflammatory cytokine and MMP production by targeting the miR-150-5p/ZBTB4 axis through JAK/STAT signaling pathway in sJIA, suggesting that MALAT1 may have a potential diagnostic biomarker for the pathogenesis and therapy of sJIA.
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