title: CCN1 Promotes VEGF Production in Osteoblasts and Induces Endothelial Progenitor Cell Angiogenesis by Inhibiting miR-126 Expression in Rheumatoid Arthritis.
abstract: Angiogenesis is the formation of new capillaries from preexisting vasculature. The perpetuation of angiogenesis plays a critical role in the pathogenesis of various disease states including rheumatoid arthritis (RA). Cysteine-rich 61 (Cyr61 or CCN1) is an important proinflammatory cytokine in RA. Here, we investigated the role of CCN1 in angiogenesis associated with vascular endothelial growth factor (VEGF) production and osteoblasts. We found higher expression of CCN1 and VEGF in synovial fluid from RA patients compared with healthy controls. CCN1 induced VEGF expression in osteoblasts and increased endothelial progenitor cells (EPCs) angiogenesis by inhibiting miR-126 via the protein kinase C-alpha (PKC-α) signaling pathway. CCN1 knockdown inhibited angiogenesis in both in vitro and in vivo models. Inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA (shRNA) ameliorated articular swelling, cartilage erosion, and angiogenesis in the ankle joint of mice with collagen-induced arthritis (CIA). Our study is the first to describe how CCN1 promotes VEGF expression in osteoblasts and increased EPCs angiogenesis in RA disease. CCN1 may serve as a potential target for RA treatment. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, China.
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Su
authors.affiliation: School of Chinese Medicine, China Medical University, Taichung, Taiwan.|Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chin-Jung
authors.initials: CJ
authors.lastname: Hsu
authors.affiliation: Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Shih-Chia
authors.initials: SC
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Wei-Cheng
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Prosthodontics, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Lih-Jyh
authors.initials: LJ
authors.lastname: Fuh
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.|Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D000328:Adult; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology*; D002645:Chickens; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D066026:Endothelial Progenitor Cells / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D010006:Osteoblasts / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D015398:Signal Transduction; D013582:Synovial Fluid / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D055515:Cysteine-Rich Protein 61; C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A; D051571:Protein Kinase C-alpha
keywords: ARTHRITIS; CCN1; OSTEOBLASTS; VEGF