title: A novel role for suppressor of cytokine signaling 3 in cartilage destruction via induction of chondrocyte desensitization toward insulin-like growth factor.
abstract: OBJECTIVE
  An important mechanism contributing to cartilage destruction in arthritis is chondrocyte desensitization toward its main anabolic factor, insulin-like growth factor 1 (IGF-1). In this study, we sought to determine the role of suppressor of cytokine signaling 3 (SOCS-3) in the induction of IGF-1 desensitization of murine chondrocytes.
  
  
  METHODS
  Chondrocyte responsiveness to IGF-1 was assessed by 35S-sulfate incorporation into proteoglycans (PGs), via aggrecan messenger RNA expression, using quantitative real-time polymerase chain reaction or insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation (Western blot analysis). IGF-1 desensitization of patellar chondrocytes was studied in zymosan-induced arthritis. IGF-1 desensitization was induced in patellar cartilage explants or the H4 chondrocyte cell line, exposed to interleukin-1alpha (IL-1alpha). SOCS-3 protein expression was assessed by immunohistochemistry or by Western blot analysis of protein extracts. The role of SOCS-3 in IGF-1 signaling was elucidated by adenoviral overexpression.
  
  
  RESULTS
  Exposure of murine articular cartilage to IL-1 caused a significant decrease in IGF-1-induced PG synthesis. This effect also occurred in inducible nitric oxide synthase-knockout mice, revealing the involvement of a secondary IL-1-induced factor other than nitric oxide. We showed that IL-1 significantly up-regulated SOCS-3 transcription and protein synthesis in H4 chondrocytes. In contrast, IL-18 was unable to induce SOCS-3 expression and failed to induce chondrocyte IGF-1 desensitization. Histologic analysis of samples from arthritic knee joints revealed high expression of SOCS-3 in chondrocytes. Through adenoviral overexpression of SOCS-3, we obtained direct evidence that SOCS-3 inhibits IGF-1-mediated cell signaling, since IRS-1 phosphorylation was reduced.
  
  
  CONCLUSIONS
  This study demonstrates that IL-1-induced SOCS-3 expression is a novel mechanism of IGF-1 desensitization in chondrocytes; in conjunction with nitric oxide it can contribute to cartilage damage during arthritis.
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: R L
authors.initials: RL
authors.lastname: Smeets
authors.forename: S
authors.initials: S
authors.lastname: Veenbergen
authors.forename: O J
authors.initials: OJ
authors.lastname: Arntz
authors.forename: M B
authors.initials: MB
authors.lastname: Bennink
authors.forename: L A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: F A J
authors.initials: FA
authors.lastname: van de Loo
mesh_terms: D000818:Animals; D002356:Cartilage / Q000473:pathology*; D019902:Chondrocytes / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D007375:Interleukin-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*
chemical_list: D007375:Interleukin-1; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007334:Insulin-Like Growth Factor I