title: The discoidin domain receptor 2/annexin A2/matrix metalloproteinase 13 loop promotes joint destruction in arthritis through promoting migration and invasion of fibroblast-like synoviocytes.
abstract: OBJECTIVE
  Discoidin domain receptor 2 (DDR-2)/matrix metalloproteinase (MMP) signaling is an important pathway involved in cartilage destruction in rheumatoid arthritis (RA). However, the molecular mechanisms of this pathway have not been clearly identified. This study was undertaken to screen key molecules involved in this pathway and evaluate their biologic functions in synovium invasion of RA.
  
  
  METHODS
  DDR-2-interacting proteins were examined in vitro by immunoprecipitation and mass spectrometry, and annexin A2 was acquired. The effects of annexin A2 on fibroblast-like synoviocyte (FLS) migration were evaluated using a Transwell invasion assay and an Erasion trace test. In Ddr2(-/-) mice with collagen-induced arthritis (CIA), hematoxylin and eosin (H&E) staining, immunohistochemical analysis, and Western blot analysis were used to assess expression of DDR-2, annexin A2, and MMP-13, as well as synovial hyperplasia. Rats with CIA were treated with lentivirus annexin A2 small interfering RNA (siRNA), and annexin A2 siRNA effects on joint damage were analyzed based upon arthritis index scores and results of micro-computed tomography and H&E staining. The differences between annexin A2 expression in clinical samples from RA and osteoarthritis patients were compared using Western blotting.
  
  
  RESULTS
  Annexin 2 was identified for the first time as a DDR-2 binding protein. It may be phosphorylated by phospho-DDR-2, leading to MMP-13 secretion. The annexin A2 phosphorylation level and MMP-13 expression level were decreased and collagen-induced joint damage greatly reduced in Ddr2(-/-) mice. Joint damage in rats with CIA was significantly ameliorated when annexin A2 was down-regulated. Annexin A2 expression and phosphorylation were elevated in human RA synovial tissue.
  
  
  CONCLUSIONS
  Annexin A2 is a key molecule in the DDR-2/annexin A2/MMP-13 loop, the activation of which contributes to joint destruction in RA, mainly through promoting invasion of FLS. Annexin A2 might therefore become a novel clinical target for RA treatment.
authors.affiliation: Fourth Military Medical University, Xi'an, China, and Ningxia Medical University, Yinchuan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Cun
authors.initials: C
authors.lastname: Zhang
authors.forename: Man
authors.initials: M
authors.lastname: Shi
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Xiaochang
authors.initials: X
authors.lastname: Xue
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shu
authors.forename: Jinyu
authors.initials: J
authors.lastname: Zhu
authors.forename: Nan
authors.initials: N
authors.lastname: Mu
authors.forename: Weina
authors.initials: W
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hao
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Gong
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000502:physiology*; D000070818:Discoidin Domain Receptors; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology
chemical_list: D017306:Annexin A2; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D053509:Matrix Metalloproteinase 13