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.
Cawston TE, Curry VA, Summers CA, Clark IM, Riley GP, Life PF, Spaull JR, Goldring MB, Koshy PJT, Rowan AD, Shingleton WD: The role of oncostatin M in animal and human connective tissue collagen turnover and its localization within the rheumatoid joint.
Rowan AD, Koshy PJT, Shingleton WD, Degnan BA, Heath J, Vernallis AB, Spaull JR, Life PF, Hudson K, Cawston TE: Synergistic effects of gp130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown.
Catterall JB, Carrere S, Koshy PJT, Degnan BA, Shingleton WD, Brinckerhoff CE, Rutter J, Cawston TE, Rowan AD: Synergistic induction of matrix metalloproteinase 1 by interleukin-1alpha and oncostatin M in human chondrocytes involves signal transducer and activator of transcription and activator protein 1 transcription factors via a novel mechanism.
Hui W, Cawston TE, Rowan AD: Transforming growth factor β1 and insulin-like growth factor 1 block collagen degradation induced by oncostatin M in combination with tumour necrosis factor α from bovine cartilage.