title: Connective tissue growth factor/CCN2 overexpression in mouse synovial lining results in transient fibrosis and cartilage damage.
abstract: OBJECTIVE
  Characteristics of osteoarthritis (OA) include cartilage damage, fibrosis, and osteophyte formation. Connective tissue growth factor (CTGF; also known as CCN2), is found in high levels in OA chondrocytes and is frequently involved in fibrosis, bone formation, and cartilage repair. The present study was therefore undertaken to investigate the potential role of CTGF in OA pathophysiology.
  
  
  METHODS
  We transfected the synovial lining of mouse knee joints with a recombinant adenovirus expressing human CTGF and measured synovial fibrosis and proteoglycan content in cartilage on days 1, 3, 7, 14, and 28. Messenger RNA (mRNA) expression in synovium and cartilage was measured on days 3, 7, and 21.
  
  
  RESULTS
  CTGF induced synovial fibrosis, as indicated by accumulation of extracellular matrix and an increase in procollagen type I-positive cells. The fibrosis reached a maximum on day 7 and had reversed by day 28. Levels of mRNA for matrix metalloproteinase 3 (MMP-3), MMP-13, ADAMTS-4, ADAMTS-5, tissue inhibitor of metalloproteinases 1 (TIMP-1), and transforming growth factor beta were elevated in the fibrotic tissue. TIMP-1 expression was elevated on day 3, while expression of other genes did not increase until day 7 or later. CTGF induced proteoglycan depletion in cartilage as early as day 1. Maximal depletion was observed on days 3-7. Cartilage damage was reduced by day 28. A high level of MMP-3 mRNA expression was found in cartilage. CTGF overexpression did not induce osteophyte formation.
  
  
  CONCLUSIONS
  CTGF induces transient fibrosis that is reversible within 28 days. Overexpression of CTGF in knee joints results in reversible cartilage damage, induced either by the high CTGF levels or via factors produced by the CTGF-induced fibrotic tissue.
authors.affiliation: St. Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
authors.forename: E N
authors.initials: EN
authors.lastname: Blaney Davidson
authors.forename: E L
authors.initials: EL
authors.lastname: Vitters
authors.forename: F M
authors.initials: FM
authors.lastname: Mooren
authors.forename: N
authors.initials: N
authors.lastname: Oliver
authors.forename: W B van den
authors.initials: WB
authors.lastname: Berg
authors.forename: P M
authors.initials: PM
authors.lastname: van der Kraan
mesh_terms: D000818:Animals; D002356:Cartilage / Q000473:pathology*; D055513:Connective Tissue Growth Factor; D005355:Fibrosis; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013583:Synovial Membrane / Q000378:metabolism*
chemical_list: C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055513:Connective Tissue Growth Factor