title: Inhibition of vascular endothelial growth factor with shRNA in chondrocytes ameliorates osteoarthritis.
abstract: Osteoarthritis (OA) is a chronic, incurable and destructive joint disease that is characterized by chondrocyte hypertrophy and cartilage degradation. Angiogenesis, mediated by the action of vascular endothelial growth factor (VEGF), is known to be a contributing factor in the pathogenesis of OA. In this study, we use a lentivirus-based approach to investigate whether VEGF knockdown would be beneficial to chondrogenesis and could prevent or slow down OA progression. We first profiled cytokines in human OA cartilage using cytokine antibody arrays. This revealed that as many as 21 angiogenesis-related cytokines were significantly upregulated in severe OA cartilage compared to mild OA samples. Next, we infected chondrocytes with VEGF small hairpin RNA (shRNA) lentivirus (LV-VEGF shRNA) and treated these cells with tumour necrosis factor alpha (TNF-α) to induce hypertrophy. The results showed that inhibition of VEGF not only enhanced chondrogenic differentiation, but also protected chondrocytes from TNF-α-induced hypertrophy. We also found that knockdown of VEGF suppressed TNF-α-induced phosphorylation of ERK1/2 in chondrocytes. Furthermore, using a surgically induced OA rat model, we showed that VEGF inhibition delayed OA progression in animals given intra-articular injection of LV-VEGF shRNA. In conclusion, in this study, we have shown that VEGF knockdown can enhance chondrogenesis and prevent OA progression, thus providing evidence that inhibition of VEGF may be a potential therapeutic approach for OA patients.
  
  
  
  Numerous pro-angiogenic factors are upregulated in severe OA cartilage. Inhibition of VEGF by shRNA protects chondrocytes from TNF-α-induced hypertrophy. Knockdown of VEGF suppresses TNF-α-induced phosphorylation of ERK1/2 in chondrocytes. VEGF inhibition delays OA progression in rat model in vivo. Inhibition of VEGF may be a potential therapeutic approach for OA patients.
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Queensland, 4059, Australia.|Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, People's Republic of China.
authors.forename: Xufang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Queensland, 4059, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Crawford
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Queensland, 4059, Australia. yin.xiao@qut.edu.au.
authors.forename: Yin
authors.initials: Y
authors.lastname: Xiao
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Angiogenesis; Chondrocyte hypertrophy; Lentivirus; Osteoarthritis; Vascular endothelial growth factor