Oncostatin M Differentially Regulates Tissue Inhibitors of Metalloproteinases TIMP‐1 and TIMP‐3 Gene Expression in Human Synovial Lining Cells

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Abstract
Tissue inhibitor of metalloproteinases (TIMP) 1, 2 and 3 are related proteins that can form complexes with all known matrix metalloproteinases (MMPs). They inhibit the action of MMPs on extracellular matrix components. The balance of MMPs and TIMPs is important for tissue remodeling and its disturbance is believed to play a crucial role in pathophysiological processes such as tumor metastasis, destruction of cartilage and fibrosis. Cytokines and growth factors were found to regulate TIMPs and MMPs in a complex manner. In order to better understand the role of TIMPs in inflammatory joint diseases we have studied in vitro the regulation of TIMP-1 and TIMP-3 by inflammatory cytokines in cultured human synovial lining cells. We found that transforming growth factor β as well as interleukin-1β induce gene expression of both TIMP-1 and TIMP-3. In contrast, oncostatin M, an interleukin-6-type cytokine produced by activated T-lymphocytes and monocytes, had a differential effect on TIMP mRNA levels. After oncostatin M treatment, TIMP-1 expression was up-regulated but basal, as well as interleukin-1β-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-h receptor induced activation of signal transducer and activator of transcription (STAT) factors in these cells and regulated TIMP-1 and TIMP-3 expression in a similar fashion as oncostatin M. Since TIMP-3 is matrix-associated whereas TIMP-1 is found in many body fluids, the role of oncostatin M during inflammatory processes might be to promote ECM degradation in the local environment but to prevent it systemically.