Chondromodulin-1 ameliorates osteoarthritis progression by inhibiting HIF-2α activity.
Hypoxia is known to stabilize hypoxia-inducible factor (HIF) and initiate angiogenic signaling cascade. However, cartilage living in hypoxia environment can maintain avascularity. It is well known that abrogation of avascularity is related to cartilage degradation in osteoarthritis (OA). The aims of present study were to investigate the role of chondromodulin-1 (ChM-1), an endogenously anti-angiogenic protein in cartilage, during chondrocyte maturation and OA progression, as well as to explore the molecular mechanisms underlying the function of ChM-1 with a focus on HIF-2α pathway.



Angiogenic-related markers were evaluated in OA cartilage and different stages of chondrocyte differentiation. Chondrocytes transfected with ChM-1 lentivirus or siRNA was treated with tumor necrosis factor (TNF-α) to investigate the role of ChM-1 in chondrocyte hypertrophic changes. In vivo study was conducted by using a surgical induced OA rat model with intra-articular injection of lentivirus ChM-1 (LV-ChM-1) or mock lentivirus (LV-GFP) control. Transcriptional activity of HIF-2α was determined by chromatin immunoprecipitation (ChIP) assay to unveil the mechanisms of ChM-1.



Majority angiogenic factors increased in severe OA cartilage, while anti-angiogenic factors including ChM-1 decreased. ChM-1 expression was strongly related with chondrocyte differentiation and chondrogenesis in vitro. ChM-1 overexpression protected chondrocytes from TNF-α induced hypertrophy, and intra-articular injection of LV-ChM-1 delayed OA progression. ChM-1 delayed HIF-2α nuclear translocation at early time-points and decreased transcriptional activity of HIF-2α on collagen type Х α1 (COL10A1), vascular endothelial growth factor A (VEGFA) and matrix metallopeptidase-13 (MMP-13).



ChM-1 maintains cartilage homeostasis by inhibiting HIF-2α induced catabolic activity and regulation of ChM-1 in cartilage may be a promising therapeutic strategy for OA.
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia; Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, PR China. Electronic address: xufang.zhang@connect.qut.edu.au.
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Zhang
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. Electronic address: i.prasadam@qut.edu.au.
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Prasadam
Key Laboratory of Oral Biomedical Engineering of Ministry of Education, Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei Province, PR China. Electronic address: fat987500@yahoo.com.cn.
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Fang
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. Electronic address: r.crawford@qut.edu.au.
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Crawford
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. Electronic address: yin.xiao@qut.edu.au.
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Xiao
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002358:Cartilage, Articular; D019902:Chondrocytes; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010003:Osteoarthritis; D051381:Rats; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C489407:Cnmd protein, rat
Angiogenesis inhibitors; Chondrocyte hypertrophy; Chondromodulin-1; Hypoxia-inducible factor 2; Osteoarthritis