ONCOSTATIN-M DIFFERENTIALLY REGULATES TISSUE INHIBITORS OF METALLOPROTEINASES TIMP-1 AND TIMP-3 GENE-EXPRESSION IN HUMAN SYNOVIAL LINING CELLS

Tissue inhibitor of metalloproteinases (TIMP) 1, 2 and 3 are related p roteins that can form complexes with all known matrix metalloproteinas es (MMPs). They inhibit the action of MMPs on extracellular matrix com ponents. The balance of MMPs and TIMPs is important for tissue remodel ing and its disturbance is believed to play a crucial role in pathophy siological processes such as tumor metastasis. destruction of cartilag e and fibrosis. Cytokines and growth factors were found to regulate TI MPs and MMPs in a complex manner. In order to better understand the ro le of TIMPs in inflammatory joint diseases we have studied in vitro th e regulation of TIMP-1 and TIMP-3 by inflammatory cytokines in culture d human synovial lining cells. We found that transforming growth facto r beta(1) as well as interleukin-1 beta induce gene expression of both TIMP-1 and TIMP-3. In contrast, oncostatin M, an interleukin-6-type c ytokine produced by activated T-lymphocytes and monocytes, had a diffe rential effect on TIMP mRNA levels. After oncostatin hi treatment. TIM P-1 expression was up-regulated but basal, as well as interleukin-1 be ta-induced, TIMP-3 expression was inhibited. Interleukin-6 itself had no effect on synovial lining cells but a complex of interleukin-6 and the soluble interleukin-6 receptor induced activation of signal transd ucer and activator of transcription (STAT) factors in these cells and regulated TIMP-1 and TIMP-3 expression in a similar fashion as oncosta tin M. Since TIMP-3 is matrix-associated whereas TIMP-1 is found in ma ny body fluids, the role of oncostatin hi during inflammatory processe s might be to promote ECM degradation in the local environment but to prevent it systemically.