interferon-γ inhibits interleukin-1β-induced matrix metalloproteinase production by synovial fibroblasts and protects articular cartilage in early arthritisinterferon-γ抑制interleukin-1β-induced滑膜成纤维细胞基质金属蛋白酶的生产和保护关节软骨在早期关节炎.pdfVIP

Page et al. Arthritis Research Therapy 2010, 12:R49 /content/12/2/R49 R E S E A R C H A R T I C L E Open Access Research article Interferon-γ inhibits interleukin-1β-induced matrix metalloproteinase production by synovial fibroblasts and protects articular cartilage in early arthritis 1 2 2 1 2 2 Charlotte E Page , Shaun Smale , Sara M Carty , Nicholas Amos , Sarah N Lauder , Rhian M Goodfellow , Peter J Richards3 3 3 2 , Simon A Jones , Nicholas Topley and Anwen S Williams* Abstract Introduction: The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis. Methods: We studied IFN-γs capacity to modulate interleukin-1β (IL-1β) induced degenerative responses using RA fibroblast-like synoviocytes (FLS), a bovine articular cartilage explant (BACE)/RA-FLS co-culture model and an experimental inflammatory arthritis model (murine antigen-induced arthritis (AIA)). Results: IFN-γ modulated IL-1β driven matrix metalloproteinases (MMP) synthesis resulting in the down-regulation of MMP-1 and MMP-3 production in vitro. IFN-γ did not affect IL-1β induced tissue inhibitor of metalloproteinase-1 (TIMP- 1) production by RA FLS but skewed the MMP/TIMP-1 balance sufficiently to attenuate glycosaminoglycan-depletion in our BACE model. IFN-γ reduced IL-1β expression in the arthritic joint and prevented cartilage degeneration on Day 3 of AIA. Conclusions: Early therapeutic intervention with IFN-γ may be critical to orchestrate tissue-protective respon