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

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 TlMPs 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 intlammatory cytokines in cultured human synovial lining cells. We found that transforming growth factor PI as well as interleukin-I@ 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-lg-induced, TlMP-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-I 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 i n the local environment but to prevent it systemically.

Induction of CCL13 expression in synovial fibroblasts highlights a significant role of oncostatin M in rheumatoid arthritis

“…So far, most studies corroborating the involvement of OSM in the development and progression of RA have highlighted its contribution to cartilage breakdown preferentially by up-regulation of MMPs and aggrecanases (18,20,22,26,46) as well as changes in the MMP:TIMP ratio in favor of MMPs (19,37). In this study, we identified OSM as the main regulator of CCL13 chemokine expression by SFs.…”

“…Neutrophils, normal dermal fibroblasts, and RASFs were generated as described previously (33)(34)(35). Lung fibroblasts were kindly provided by P. Marynen (University of Leuven, Leuven, Belgium [36]), and the normal SFs and normal cervical fibroblasts were provided by E. Van de Leur (RWTH Aachen University Hospital, Aachen, Germany [37,38]). Primary human monocytes were isolated from fresh blood using the Dynal Monocyte Negative Isolation Kit as described by the manufacturer (Invitrogen).…”

Influence of LPS, TNF, TGF-�1 and IL-4 on the expression of MMPs, TIMPs and selected cytokines in rat synovial membranes incubated in vitro

“…Production of TIMP2 in dermal fibroblasts at the mRNA and protein levels was shown to be stimulated by IL-4, but not by TGF-ß1 (112). TGF-ß1 has been shown to induce expression of both TIMP1 and TIMP3 in human synovial lining cells (113). Moreover, increased expression of TIMP3, under influence of TGF-ß1, has been observed in fibroblasts (114).…”

Box 2 Region of the Oncostatin M Receptor Determines Specificity for Recruitment of Janus Kinases and STAT5 Activation

“…However, it also induces the growth of AIDS-associated Kaposi's sarcoma cells (15,16). Because of its ability to induce TIMP-1 and TIMP-3, pro-fibrotic properties have also been attributed to OSM (17)(18)(19). Indeed, transgenic mice expressing OSM in islet ␤-cells develop severe fibrosis (20).…”