PGE2 Inhibits MMP Expression by Suppressing MKK4-JNK MAP Kinase-c-JUN Pathway via EP4 in Human Articular Chondrocytes
PGE2 Inhibits MMP Expression by Suppressing MKK4-JNK MAP Kinase-c-JUN Pathway via EP4 in Human Articular Chondrocytes
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DOI：
10.1002/jcb.22421
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发表时间：
2010-02-01
影响因子：
4
通讯作者：
Nakamura, Takashi
中科院分区：
文献类型：
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作者：
Nishitani, Kohei;Ito, Hiromu;Nakamura, Takashi
前列腺素E2(PGE2)是一种促炎介质。前列腺素E_2维持包括关节软骨在内的许多器官的动态平衡。先前的一份报告表明，持续抑制PGF2会加速骨关节炎(OA)的进展。虽然PGE2抑制了几种细胞中基质金属蛋白酶(MMPs)的表达，但PGE2对关节软骨细胞中MMPs表达的直接影响却知之甚少。本研究旨在探讨前列腺素E_1(PGE_1)对IL-1β诱导的关节软骨细胞基质金属蛋白酶-1和基质金属蛋白酶-13表达及细胞内信号转导的直接影响。免疫印迹结果显示，PGF2对IL-1β诱导的骨关节炎和正常软骨细胞中的基质金属蛋白酶-1和基质金属蛋白酶-13的表达均有抑制作用，酶联免疫吸附试验和关节软骨组织块培养的免疫组织化学进一步证实了这一点。EP4激动剂ONO-AE1-329模拟PGF2的抑制作用，而EP4拮抗剂ONO-AE3-208则阻断(Lie效应)。PGE2抑制JNK和ERK MAP激酶的磷酸化，但只有特异性siRNA抑制JNK的作用与PGE2相似。PGF2进一步抑制MKK4的磷酸化而不抑制MKK7的磷酸化，并抑制c-jun降低基质金属蛋白酶-1和基质金属蛋白酶-13的表达。这些结果表明，PGE2通过抑制MKK4-JNK MAP-KK-c-Jun通路，抑制IL-1β诱导的基质金属蛋白酶-1和基质金属蛋白酶-13的产生。J.细胞。生物化学。2010年，109：425-433。(C)2009年Wiley-Liss，Inc.
Prostaglandin E2 (PGE2) is one of pro-inflammatory mediators. PGE2 maintains the homeostasis of many organ including articular cartilage. and a previous report showed that continuous inhibition of PGF2 accelerates the progression of osteoarthritis (OA). While PGE2 inhibits matrix metalloprotease (MMP) expression in Several types of cells, little is known on direct effects of PGE2 on MMP expression in articular chondrocytes. The objective of this study Was 10 investigate direct effects of PGE1 on IL-1 beta-induced MMP-1 and MMP-13 expression and the intracellular signaling in articular chondrocytes. PGF2 showed inhibitory effects on IL-1 beta-induced MMP-1 and MMP-13 expression demonstrated by immunoblotting both in OA and normal chondrocytes, which was further confirmed by enzyme-linked immunosorbent assay and immunohistochemistry of explant cultures of articular cartilages. An EP4 agonist, ONO-AE1-329, mimicked the inhibitory effect of PGF2, while an EP4 antagonist, ONO-AE3-208, blocked (lie effects. PGE2 Suppressed the phosphorylation of JNK and ERK MAP kinases, but only knockdown of JNK by specific siRNA mimicked the effect of PGE2. PGF2 further inhibited the phosphorylation of MKK4 without suppression of MKK7 phosphorylation, and of c-JUN to decrease expression levels of MMP-1 and MMP-13. These results demonstrate that PGE2 inhibits IL-1 beta-induced MMP-1 and MMP-13 productions via EP4 by suppressing MKK4-JNK MAP kinase-c-JUN pathway. J. Cell. Biochem. 109: 425-433, 2010. (C) 2009 Wiley-Liss, Inc.