PGE2 inhibits chondrocyte differentiation through PKA and PKC signaling
PGE2 inhibits chondrocyte differentiation through PKA and PKC signaling
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DOI：
10.1016/j.yexcr.2004.06.019
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发表时间：
2004-10-15
影响因子：
3.7
通讯作者：
O'Keefe, RJ
中科院分区：
文献类型：
--
作者：
Li, TF;Zuscik, MJ;O'Keefe, RJ
前列腺素是花生四烯酸普遍存在的代谢物，环氧合酶抑制剂可抑制其产生和分泌。环氧合酶-2功能丧失的动物修复性骨形成减少，但前列腺素在软骨内骨形成中的作用尚不明确。探讨前列腺素E_2(PGE_2)对鸡生长板软骨细胞(GPC)分化的调节作用。在10(-6)M时，PGE2、PGD2、PGF2pha和PGJ2均抑制colX的表达，约80%，而PGE2是cAMP反应元件(CRE)介导的转录的最强激活剂。PGE2剂量依赖性地抑制分化相关基因colX、VEGF、MMP13和碱性磷酸酶基因的表达，并在低至10(-10)M时显著抑制酶活性，诱导cAMP反应元件结合蛋白(CREB)磷酸化，使c-Fos蛋白水平升高5min，并激活Cre-Luc、AP-1-Luc和c-Fos启动子结构的转录。蛋白激酶A(PKA)抑制剂H-89完全阻断PGE2介导的Cre-Luc和c-Fos启动子-Luc的诱导，并部分抑制AP-1-Luc的诱导，而蛋白激酶C(PKC)抑制剂GO-6976部分抑制这三个启动子，表明这些信号通路之间存在显著的串扰。PGE2对colX基因表达的抑制依赖于PKA和PKC信号。这些观察结果显示了前列腺素对软骨细胞成熟的有效调节作用，并显示了PKA和PKC信号在PGE2调节事件中的作用。(C)2004 Elsevier Inc.保留所有权利。
Prostaglandins are ubiquitous metabolites of arachidonic acid, and cyclooxygenase inhibitors prevent their production and secretion. Animals with loss of cyclooxygenase-2 function have reduced reparative bone formation, but the role of prostaglandins during endochondral bone formation is not defined. The role of PGE2 as a regulator of chondrocyte differentiation in chick growth plate chondrocytes (GPCs) was examined. While PGE2, PGD2, PGF2alpha, and PGJ2 all inhibited colX expression, approximately 80% at 10(-6) M, PGE2 was the most potent activator of cAMP response element (CRE)-mediated transcription. PGE2 dose-dependently inhibited the expression of the differentiation-related genes, colX, VEGF, MMP-13, and alkaline phosphatase gene, and enzyme activity with significant effects at concentrations as low as 10(-10) M. PGE2 induced cyclic AMP response element binding protein (CREB) phosphorylation and increased c-Fos protein levels by 5 min, and activated transcription at CRE-Luc, AP-1-Luc, and c-Fos promoter constructs. The protein kinase A (PKA) inhibitor, H-89, completely blocked PGE2-mediated induction of CRE-Luc and c-Fos promoter-Luc promoters, and partially inhibited induction of AP-1-Luc, while the protein kinase C (PKC) inhibitor Go-6976 partially inhibited all three promoters, demonstrating substantial cross-talk between these signaling pathways. PGE2 inhibition of colX gene expression was dependent upon both PKA and PKC signaling. These observations demonstrate potent prostaglandin regulatory effects on chondrocyte maturation and show a role for both PKA and PKC signaling in PGE2 regulatory events. (C) 2004 Elsevier Inc. All rights reserved.