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Synergistic interactions of proinflammatory cytokines with oncostatin M: implications for joint destruction
Arthritis Res Ther volume 5, Article number: 71 (2003)
Oncostatin M (OSM) is an IL-6 family cytokine that we have previously shown to synergise with IL-1 to induce cartilage proteoglycan and collagen degradation in a cartilage explant culture system, and these observations now extend to IL-6 [1, 2]. A significant finding of these studies was the synergistic induction of the collagenase, matrix metalloproteinase (MMP)-1, which occurs via interplay between the JAK/STAT, AP-1 and MAPK pathways . These studies have important implications for inflammatory joint disease since OSM (and, indeed, IL-6) have been proposed to be protective in rheumatoid arthritis. Recently, we also demonstrated that OSM can exacerbate the effects of another important proinflammatory mediator, tumour necrosis factor (TNF)-α . In order to assess the effects of these cytokine combinations in vivo, we have assessed the effects of intra-articular gene transfer of OSM in combination with either IL-1 or TNF-α on murine knee joints using recombinant adenovirus.
Engineered adenoviruses were administered for only 7 days, after which time joints were fixed, decalcified and sectioned. Histological analyses indicated marked synovial hyperplasia and inflammatory cell infiltration for IL-1-treated, TNF-α-treated and OSM-treated joints, but not in controls (joints treated with an 'empty' adenovirus). The inflammation was more pronounced for both the OSM + IL-1 and OSM + TNF-α combinations with evidence of cartilage and bone destruction. Significant loss of both proteoglycan and collagen was also seen for these combinations, and immunohistochemistry revealed an increased expression of MMPs with decreased tissue inhibitors of metalloproteinases in both articular cartilage and synovium. The effects of these combinations were significantly greater than those seen with any of the cytokines alone. Taken together, these data confirm that, in vivo, OSM can significantly exacerbate the effects of both IL-1 and TNF-α, resulting in inflammation and tissue destruction characteristic of that seen in rheumatoid arthritis. This study provides further evidence to implicate the upregulation of MMPs as a key factor in joint pathology, and further supports the concept of combinatorial therapeutic approaches for the treatment of inflammatory joint diseases.
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Cawston, T., Wang, H., Richards, C. et al. Synergistic interactions of proinflammatory cytokines with oncostatin M: implications for joint destruction. Arthritis Res Ther 5 (Suppl 3), 71 (2003). https://doi.org/10.1186/ar872