ONCOSTATIN-M UP-REGULATES TISSUE INHIBITOR OF METALLOPROTEINASES-3 GENE-EXPRESSION IN ARTICULAR CHONDROCYTES VIA DE-NOVO TRANSCRIPTION, PROTEIN-SYNTHESIS, AND TYROSINE KINASE-ACTIVATED AND MITOGEN-ACTIVATED PROTEIN KINASE-DEPENDENT MECHANISMS

Cytokines and growth factors regulate physiologic and pathologic turn- over of cartilage extracellular matrix (ECM)by altering the balance be tween tissue inhibitors of metalloproteinases (TIMPs) and matrix metal loproteinases (MMPs), Oncostatin M (OSM) is a cytokine of the IL-6 fam ily whose levels are increased in the serum and synovial fluids of pat ients with rheumatoid arthritis. We examined responsiveness of the TIM P-3 gene to OSM in articular chondrocytes and studied the regulatory a nd signaling mechanisms of this response. OSM induced TIMP-3 mRNA and protein expression in a dose- and time-dependent fashion, Concomitantl y, stromelysin-1 and collagenase-1 RNA and activities were also induce d. A cartilage matrix growth factor, TGF-P, induced TIMP-3, but combin ed OSM and TGF-P did not further increase the extent of induction, sug gesting a lack of synergy behueen the two. OSM induction of TIMP-3 gen e expression was dependent upon de novo protein synthesis and transcri ption, RNA decay Lime-courses suggested that the OSM-mediated increase of TIMP-3 RNA was not due to enhanced message stability and, along wi th inhibition by actinomycin-D, suggested a transcriptional control. T he antiinflammatory glucacorticoid, dexamethasone, down-regulated this augmentation, Investigation of the signaling mechanisms revealed that protein tyrosine kinase inhibitors genistein and herbimycin A, as wel l as the specific mitogen-activated protein kinase (MAPK) kinase inhib itor PD98059, suppressed OSM-induced TIMP-3 message expression, sugges ting the involvement of tyrosine kinases and mitogen-activated protein kinase cascades in the signaling of OSM leading to TIMP-3 RNA enhance ment, Thus OSM can potentially alter the cartilage matrix metabolism b y regulating genes like TIMP-3 and matrix metalloproteinases.