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

• Published in: The Journal of immunology (1950) Vol. 166; no. 5; pp. 3491 - 3498
• Main Authors: Li, Wen Qing, Dehnade, Faramaze, Zafarullah, Muhammad
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.03.2001
• Subjects: Animals; Cattle; Cells, Cultured; Chondrocytes - drug effects; Chondrocytes - enzymology; Chondrocytes - metabolism; collagenase 3; Curcumin - pharmacology; DNA - metabolism; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Humans; Jak kinase; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases - biosynthesis; Matrix Metalloproteinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Oncostatin M; p38 Mitogen-Activated Protein Kinases; Peptides - antagonists & inhibitors; Peptides - pharmacology; Peptides - physiology; Phosphorylation - drug effects; Protein Binding - drug effects; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Protein-Tyrosine Kinases - physiology; Proto-Oncogene Proteins; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - biosynthesis; Signal Transduction - physiology; Stat1 protein; STAT1 Transcription Factor; TIMP-3 protein; Tissue Inhibitor of Metalloproteinase-3 - antagonists & inhibitors; Tissue Inhibitor of Metalloproteinase-3 - biosynthesis; Tissue Inhibitor of Metalloproteinase-3 - genetics; Trans-Activators - antagonists & inhibitors; Trans-Activators - metabolism; Trans-Activators - physiology; Tyrphostins - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.5.3491

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.