Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway
Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway
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DOI：
10.4049/jimmunol.166.5.3491
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发表时间：
2001-03-01
影响因子：
4.4
通讯作者：
Zafarullah, M
中科院分区：
文献类型：
--
作者：
Li, WQ;Dehnade, F;Zafarullah, M
抑瘤素M（OSM）是细胞因子IL-6超家族的成员，在类风湿性关节炎患者中升高，并且与IL-1协同作用，通过基质金属蛋白酶（MMP）促进软骨退变。我们以前已经表明，OSM诱导MMP和金属蛋白酶组织抑制剂-3（TIMP-3）的基因表达的蛋白酪氨酸激酶依赖的机制在软骨细胞。在本研究中，我们研究了OSM诱导MMP和TIMP-3基因的信号通路。我们证明，OSM迅速刺激磷酸化的Janus激酶（JAK）1，JAK 2，JAK 3，和STAT 1以及细胞外信号调节激酶（ERK）1/2，p38，和c-Jun IV-末端激酶1/2有丝分裂原活化蛋白激酶在原代牛和人软骨细胞。JAK 3特异性抑制剂阻断OSM刺激的STAT 1酪氨酸磷酸化、STAT 1的DNA结合活性以及胶原酶-1（MMP-1）、基质溶解素-1（MMP-3）、胶原酶-3（MMP-13）和TIMP-3 RNA表达。相比之下，JAK 2特异性抑制剂AG 490对这些事件没有影响。OSM诱导的ERK 1/2活化也不受这些抑制剂的影响。同样，姜黄素（二阿魏酰甲烷），一种抗炎剂，抑制OSM刺激的STAT 1磷酸化，STAT 1的DNA结合活性，和c-Jun N-末端激酶激活，而不影响JAK 1，JAK 2，JAK 3，ERK 1/2和p38磷酸化。姜黄素还抑制OSM诱导的MMP-1、MMP-3、MMP-13和TIMP-3基因表达。因此，OSM通过激活JAK/STAT和丝裂原活化蛋白激酶信号通路诱导软骨细胞中的MMP和TIMP-3基因，并且干扰这些通路可能是阻断OSM的分解代谢作用的有用方法。
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 IV-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.