Oncostatin M-Induced Matrix Metalloproteinase and Tissue Inhibitor of Metalloproteinase-3 Genes Expression in Chondrocytes Requires Janus Kinase/STAT Signaling Pathway

Abstract

Oncostatin M (OSM), a member of the IL-6 superfamily of cytokines, is elevated in patients with rheumatoid arthritis and, in synergy with IL-1, promotes cartilage degeneration by matrix metalloproteinases (MMPs). We have previously shown that OSM induces MMP and tissue inhibitor of metalloproteinase-3 (TIMP-3) gene expression in chondrocytes by protein tyrosine kinase-dependent mechanisms. In the present study, we investigated signaling pathways regulating the induction of MMP and TIMP-3 genes by OSM. We demonstrate that OSM rapidly stimulated phosphorylation of Janus kinase (JAK) 1, JAK2, JAK3, and STAT1 as well as extracellular signal-regulated kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase 1/2 mitogen-activated protein kinases in primary bovine and human chondrocytes. A JAK3-specific inhibitor blocked OSM-stimulated STAT1 tyrosine phosphorylation, DNA-binding activity of STAT1 as well as collagenase-1 (MMP-1), stromelysin-1 (MMP-3), collagenase-3 (MMP-13), and TIMP-3 RNA expression. In contrast, a JAK2-specific inhibitor, AG490, had no impact on these events. OSM-induced ERK1/2 activation was also not affected by these inhibitors. Similarly, curcumin (diferuloylmethane), an anti-inflammatory agent, suppressed OSM-stimulated STAT1 phosphorylation, DNA-binding activity of STAT1, and c-Jun N-terminal kinase activation without affecting JAK1, JAK2, JAK3, ERK1/2, and p38 phosphorylation. Curcumin also inhibited OSM-induced MMP-1, MMP-3, MMP-13, and TIMP-3 gene expression. Thus, OSM induces MMP and TIMP-3 genes in chondrocytes by activating JAK/STAT and mitogen-activated protein kinase signaling cascades, and interference with these pathways may be a useful approach to block the catabolic actions of OSM.

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

“…Many MMPs possess transcription factorbinding motifs such as AP1, AP2, NF-kB, PEA3, Sp1 and STAT elements in their 5 0 -flanking regulatory DNA sequences. 48,49 As a member of the CITED family of transcriptional co-activators, the promoter of CITED2 contains multiple STAT-binding sites, consistent with its responsiveness to different cytokines. 50,51 In addition, crosstalk between the IFN-a system and a member of the nuclear hormone receptor-peroxisome proliferator-activated receptor a (PPARa) is suggested by CITED2, which is a known PPARa co-activator.…”

Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration

“…It is likely that the infiltrating macrophages or neutrophils secrete OSM that in turn functions to recruit additional inflammatory cells into the injured muscles and to prevent premature differentiation of myoblasts [32]. In addition to a direct effect on myoblasts shown in this report, OSM may also contribute to muscle regeneration by regulating muscle stem cell niche, as OSM/ OSMR is known to regulate the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases [69][70][71]. The balanced action of these two classes of proteins regulates the integrity of extracellular matrix and is essential during tissue remodeling and repair.…”

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

“…JAK-STAT together with MAPK pathways was required to maximize the expression of MMP genes in normal fibroblasts and astrocytes in response to oncostatin M, a member of the IL-6 super family of cytokines (Korzus et al, 1997). In arthritis, chemical inhibitors to block JAK-STAT and MAPK pathways and MMP have been implicated to prevent inflammation and protect cartilage from the oncostatin M-stimulated degradation by MMP (Li et al, 2001). However, the mechanism by which the EGFR-induced STAT signaling leads to the activation of MMP genes remains to be understood.…”