title: Cyr61 participates in the pathogenesis of rheumatoid arthritis via promoting MMP-3 expression by fibroblast-like synoviocytes.
abstract: OBJECTIVE
  The aim of this study was to investigate the effect and potential mechanism of Cysteine-rich 61 (Cyr61) on stimulating MMP-3 expression by fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients.
  
  
  METHODS
  Primarily cultured RA FLS were treated with exogenous Cyr61 protein or Cyr61-siRNA, then, MMP-3 expression was analyzed by real-time PCR, western blotting and ELISA. Signal transduction pathways in Cyr61-induced MMP-3 production were examined by real-time PCR, western blotting, confocal microscopy, luciferase reporter assay. Mice with collagen-induced arthritis (CIA) were treated with anti-Cyr61 monoclonal antibodies (mAb), or IgG1 as control and MMP-3 in the joint was detected by IHC, real-time PCR and western blotting.
  
  
  RESULTS
  High expressed MMP-3 and Cyr61 were positively correlated in RA ST; Cyr61 stimulated MMP-3 production in FLS of RA patients in an IL-1β and TNF-α independent manner. Cyr61 induced MMP-3 could further enhance the invasive ability of RA FLS. Mechanistically, we found that Cyr61 promoted MMP-3 production via the P38, JNK-dependent AP-1 signaling pathway. Blockage of Cyr61 function with monoclonal antibody could decrease MMP-3 expression in the joints of CIA mice.
  
  
  CONCLUSIONS
  This study provides new evidence that Cyr61 participates in RA pathogenesis not only as a pro-inflammatory factor but also plays a key role in bone erosion via promoting MMP-3 expression. We suggest that targeting of Cyr61 may represent a potential strategy in RA treatment.
authors: a Department of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences , Shanghai Jiao Tong University School of Medicine , Shanghai , China.
authors: Tianhang
authors: T
authors: Zhai
authors: b Department of Bone Surgery, Institute of Arthritis Research , Shanghai Academy of Chinese Medical Sciences , Shanghai , China.
authors: Chenxin
authors: C
authors: Gao
authors: a Department of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences , Shanghai Jiao Tong University School of Medicine , Shanghai , China.
authors: Rongfen
authors: R
authors: Huo
authors: c Department of Laboratory Medicine , Affiliated Tongren Hospital of Shanghai Jiao Tong University School of Medicine , Shanghai , China.
authors: Huiming
authors: H
authors: Sheng
authors: b Department of Bone Surgery, Institute of Arthritis Research , Shanghai Academy of Chinese Medical Sciences , Shanghai , China.
authors: Songtao
authors: S
authors: Sun
authors: b Department of Bone Surgery, Institute of Arthritis Research , Shanghai Academy of Chinese Medical Sciences , Shanghai , China.
authors: Jun
authors: J
authors: Xie
authors: b Department of Bone Surgery, Institute of Arthritis Research , Shanghai Academy of Chinese Medical Sciences , Shanghai , China.
authors: Yong
authors: Y
authors: He
authors: b Department of Bone Surgery, Institute of Arthritis Research , Shanghai Academy of Chinese Medical Sciences , Shanghai , China.
authors: Huali
authors: H
authors: Gao
authors: a Department of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences , Shanghai Jiao Tong University School of Medicine , Shanghai , China.
authors: Huidan
authors: H
authors: Li
authors: a Department of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences , Shanghai Jiao Tong University School of Medicine , Shanghai , China.
authors: Jie
authors: J
authors: Zhang
authors: a Department of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences , Shanghai Jiao Tong University School of Medicine , Shanghai , China.
authors: Haichuan
authors: H
authors: Li
authors: a Department of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences , Shanghai Jiao Tong University School of Medicine , Shanghai , China.|d Department of Rheumatoloy , Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine , Shanghai , China , and.
authors: Yue
authors: Y
authors: Sun
authors: a Department of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences , Shanghai Jiao Tong University School of Medicine , Shanghai , China.|e Department of Laboratory Medicine , The First Affiliated Hospital of Fujian Medical University , Fuzhou , China.
authors: Jinpiao
authors: J
authors: Lin
authors: a Department of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences , Shanghai Jiao Tong University School of Medicine , Shanghai , China.
authors: Baihua
authors: B
authors: Shen
authors: b Department of Bone Surgery, Institute of Arthritis Research , Shanghai Academy of Chinese Medical Sciences , Shanghai , China.
authors: Lianbo
authors: L
authors: Xiao
authors: a Department of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences , Shanghai Jiao Tong University School of Medicine , Shanghai , China.
authors: Ningli
authors: N
authors: Li
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D000070918:Synoviocytes / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3
keywords: Cyr61; Fibroblast-like synoviocytes; MMP-3; Rheumatoid arthritis; Tissue damage