Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STATsignaling pathway

Oncostatin M (OSM), a member of the IL-6 superfamily of cytokines, is eleva ted in patients with rheumatoid arthritis and, in synergy with IL-1, promot es cartilage degeneration by matrix metalloproteinases (MMPs). We have prev iously shown that OSM induces MMP and tissue inhibitor of metalloproteinase -3 (TIMP-3) gene expression in chondrocytes by protein tyrosine kinase-depe ndent mechanisms. In the present study, we investigated signaling pathways regulating the induction of MMP and TIMP-3 genes by OSM. We demonstrate tha t OSM rapidly stimulated phosphorylation of Janus kinase (JAK) 1, JAK2, JAK 3, and STAT1 as well as extracellular signal-regulated kinase (ERK) 1/2, p3 8, and c-Jun IV-terminal kinase 1/2 mitogen-activated protein kinases in pr imary bovine and human chondrocytes. A JAK3-specific inhibitor blocked OSM- stimulated STAT1 tyrosine phosphorylation, DNA-binding activity of STAT1 as well as collagenase-1 (MMP-1), stromelysin-1 (MMP-3), collagenase-3 (MMP-1 3), and TIMP-3 RNA expression. In contrast, a JAK2-specific inhibitor, AG49 0, had no impact on these events. OSM-induced ERK1/2 activation was also no t affected by these inhibitors. Similarly, curcumin (diferuloylmethane), an anti-inflammatory agent, suppressed OSM-stimulated STAT1 phosphorylation, DNA-binding activity of STAT1, and c-Jun N-terminal kinase activation witho ut affecting JAK1, JAK2, JAK3, ERK1/2, and p38 phosphorylation. Curcumin al so inhibited OSM-induced MMP-1, MMP-3, MMP-13, and TIMP-3 gene expression. Thus, OSM induces MMP and TIMP-3 genes in chondrocytes by activating JAK/ST AT and mitogen-activated protein kinase signaling cascades, and interferenc e with these pathways may be a useful approach to block the catabolic actio ns of OSM.