Human osteoarthritic chondrocytes are impaired in matrix metalloproteinase-13 inhibition by IFN-γ due to reduced IFN-γ receptor levels

Rasheed Ahmad, M. El Mabrouk, J. Sylvester, M. Zafarullah

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Objective: Human osteoarthritic (OA) cartilage type-II collagen is preferentially cleaved by the proinflammatory cytokine-induced matrix metalloproteinases-13 (MMP-13). Interferon-gamma (IFN-γ) potently inhibits interleukin-1 (IL-1)-induced MMP-13 expression in healthy chondrocytes. Our goal was to study the previously unknown impact of IFN-γ on MMP-13 in OA and compare the levels and functional activity of IFN-γ receptor (IFN-γR1) in healthy and OA chondrocytes. Methods: Chondrocytes were obtained from OA patients and non-arthritic control subjects and treated with IL-1 + or - IFN-γ. MMP-13 mRNA and protein expression were measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. IFN-γR1 expression was assessed by flow cytometry, immunoprecipitation and immunohistochemistry with fluorescein-labeled antibody. IFN-γR1 was neutralized with its antibody and signal transducer and activator of transcription 1 (STAT1) phosphorylation analyzed by Western blotting. OA chondrocytes were also transfected with control and IFN-γR1 expression vectors. Results: OA chondrocytes displayed a drastically impaired MMP-13 suppression by IFN-γ compared to control cells. IFN-γR1 levels were significantly decreased in OA chondrocytes as assessed by flow cytometry, immunoprecipitation and immunohistochemistry. Consequently, IFN-γ-stimulated STAT1 phosphorylation mediated by IFN-γR1 was also considerably reduced in OA patient chondrocytes. IFN-γR1 overexpression in OA cells restored MMP-13 suppression by IFN-γ. Conclusions: Ability of IFN-γ to suppress IL-1-induced MMP-13 expression is diminished in OA chondrocytes due to decreased IFN-γR1 levels, activity and impaired downstream signal transduction. Therefore, IFN-γR1 modulation and weakened endogenous IFN-γ response may be important mechanisms in OA pathogenesis and cartilage degradation.

Original languageEnglish
Pages (from-to)1049-1055
Number of pages7
JournalOsteoarthritis and Cartilage
Volume17
Issue number8
DOIs
Publication statusPublished - 1 Aug 2009

Keywords

  • Interferon-gamma
  • Matrix metalloproteinase-13
  • Osteoarthritis
  • Receptor
  • Signal transduction

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