Oncostatin M in combination with tumor necrosis factor ? induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo
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OBJECTIVE: To determine the effects of the proinflammatory cytokine combination of oncostatin M (OSM) and tumor necrosis factor alpha (TNFalpha) on cartilage destruction in both in vitro and in vivo model systems. METHODS: The release of collagen and proteoglycan was assessed in bovine cartilage explant cultures, while messenger RNA (mRNA) from bovine chondrocytes was analyzed by Northern blotting. Immunohistochemistry was performed on sections prepared from murine joints following injection of adenovirus vectors encoding murine OSM and/or murine TNFalpha. RESULTS: The combination of OSM + TNFalpha induced significant collagen release from bovine cartilage, accompanied by high levels of active collagenolytic activity. Northern blot analysis indicated that this cytokine combination synergistically induced matrix metalloproteinase 1 (MMP-1), MMP-3, and MMP-13 mRNA. The in vivo data clearly indicated that OSM + TNFalpha overexpression increased MMP levels and decreased levels of tissue inhibitor of metalloproteinases 1 (TIMP-1). Specifically, OSM + TNFalpha induced marked synovial hyperplasia, inflammation, and cartilage and bone destruction with a concomitant increase in MMP expression in both cartilage and synovium and decreased TIMP-1 expression in the articular cartilage. These effects were markedly greater than those seen with either cytokine alone. CONCLUSION: This study demonstrates that OSM + TNFalpha represents a potent proinflammatory cytokine combination that markedly induces MMP production in both cartilage and synovium, thus promoting joint destruction.
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