OSM Induction of Chondrocyte MMP and TIMP-3 Gene Expression

Figure 1
Figure 1. Oncostatin M (OSM) induces human and bovine chondrocyte MMP-1, MMP-3 and MMP-13, and bovine chondrocyte TIMP-3 mRNA. This induction involves activation of the Jak/Stat signaling pathway.

Oncostatin M (OSM), an IL-6 family member, is a multifunctional cytokine affecting the growth and differentiation of numerous cell types.1,2 OSM is produced by activated T lymphocytes and monocytes3 and can induce expression of various matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).4-7 It is present in the synovial fluid of rheumatoid arthritis (RA) patients and has been implicated in promoting cartilage collagen destruction.8-11

OSM increases production of MMP-1, MMP-3, and MMP-13 (i.e. the major MMPs implicated in cartilage degradation) in both human and bovine chondrocytes (see Figure 1). This suggests common signaling pathways and a catabolic role for this cytokine.4,7,9,12 Until recently, however, the OSM signaling pathway for chondrocytes had not been identified. IL-6 family members, including OSM, have been shown to induce the Jak (Janus kinase)/Stat (signal transducers and activators of transcription) signaling pathway in several other systems,13 thus implicating a potential role for this signaling pathway in chondrocytes as well.

Li et al.14 demonstrated that OSM can induce MMP and TIMP mRNA in primary chondrocytes by activation of the Jak/Stat pathway. OSM induction of human and bovine MMP-1, MMP-3 and MMP-13, and bovine TIMP-3 mRNA is dose-dependent (10-50 ng/mL) and involves the stimulation of phosphorylation of several Jak/Stat proteins. OSM, added in combination with a specific Jak-3 inhibitor, results in reduced phosphorylation of Stat 1 in a dose-dependent manner. OSM-induced gene expression of MMP-1, MMP-3, and MMP-13 is also suppressed, thus suggesting Jak-3 is an important signaling intermediary for TIMP-3 and MMP induction by OSM. Curcumin, an anti-inflammatory agent, inhibits OSM-stimulated phosphorylation of Stat 1 in a dose-dependent manner as well but has no impact on Jak activation. Curcumin also down-regulates TIMP-3 and MMP gene expression normally enhanced by OSM in a mode similar to that observed for the Jak-3 inhibitor. The Jak-3 inhibitor and curcumin both down-regulate Stat 1 DNA-binding activity suggesting Stat 1 activation may be mediated by Jak-3. Collectively, these results strongly support the pivotal role of the Jak/Stat pathway in OSM-induction of MMP and TIMP-3 expression in chondrocytes.14 Inhibiting this signaling pathway may be an effective approach in preventing cartilage destruction induced by OSM.


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