Murine oncostatin M stimulates mouse synovial fibroblasts in vitro and induces inflammation and destruction in mouse joints in vivo

Oncostatin M (OSM) is st multifunctional cytokine, a member of the interleu kin-6/leukemia inhibitory factor (IL-6/LIF) family, that can regulate a num ber of connective-tissue cell types irt vitro including cartilage and synov ial tissue-derived fibroblasts, however its role in joint inflammation in v ivo is not clear. We have analyzed murine OSM (muOSM) activity in vitro and kt vivo in mouse joint tissue, to determine the potential role of this cyt okine in local joint inflammation and pathology. The effects of muOSM and o ther IL-6/LIF cytokines on mouse synovial fibroblast cultures were assessed in vitro and showed induction of monocyte chemotactic protein-1, interleuk in-6, and tissue inhibitor metalloproteinase-1, as well as enhancement of c olony growth in soft agarose culture. Other IL-6/LIF cytokines including IL -6, LIF, or cardiotrophin-1, did not have such effects when tested at relat ively high concentrations (20 ng/ml), To assess effects of muOSM in articul ar joints in vivo, we used recombinant adenovirus expressing muOSM cDNA. (A dmuOSM) and injected purified recombinant virus (10(6) to 10(8) pfu) intra- articularly into the knees of various mouse strains. Histological analysis revealed dramatic alterations in the synovium but not in synovium of knees treated with the control virus Ad-d170 or knees treated with Adm-IL-6 encod ing biologically active murine IL-6, AdmuOSM effects were characterized by increases in the synovial cell proliferation, infiltration of mononuclear c ells, and increases in extracellular matrix deposition that were evident at day 4, but much more marked at days 7, 14, and 21 after administration. Th e synovium took on characteristics similar to pannus and appeared to contac t and invade cartilage. Collectively, these results provide good evidence t hat OSM regulates synovial fibroblast function differently than other IL-6- type cytokines, and can induce a proliferative invasive phenotype of synovi um in vivo in mice on overexpression, We suggest that OSM may contribute to pathology in arthritis.