ATF6 upregulates XBP1S and inhibits ER stress-mediated apoptosis in osteoarthritis cartilage
ATF6 upregulates XBP1S and inhibits ER stress-mediated apoptosis in osteoarthritis cartilage
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ATF6 上调 XBP1S 并抑制骨关节炎软骨中 ER 应激介导的细胞凋亡
DOI：
10.1016/j.cellsig.2013.11.018
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发表时间：
2014-02-01
影响因子：
4.8
通讯作者：
Jiang, Rong
中科院分区：
文献类型：
--
作者：
Guo, Feng-Jin;Xiong, Zhangyuan;Jiang, Rong
正如我们以前报道的，转录因子XBP 1 S增强BMP 2诱导的软骨细胞分化，并作为软骨细胞肥大的正介质。本研究的目的是确定（1）XBP 1 S是否影响骨关节炎（OA）中ER应激介导的细胞凋亡;（2）ATF 6是否调节OA软骨中的IRE 1/XBP 1信号通路;（3）影响骨关节炎中细胞凋亡的相关分子以及该过程的分子事件。在此，我们检测并发现ER应激相关分子在OA患者中被激活，特别是XBRIS剪接和表达通过TNF-α和IL-1 β治疗显著增加。转录因子ATF 6可特异性结合于XBP 1基因的启动子，增强IRE 1 α剪接的XBP 1 S在骨关节炎软骨中的表达。此外，siXBP 1 S可以增强ER应激介导的细胞凋亡和骨关节炎中的主要基质降解。而AdXBP 1 S可抑制ER应激介导的OA软骨细胞凋亡和TNF α诱导的亚硝酸盐产生。总之，我们的观察证明了XBP 1 S在骨关节炎中的重要性。ATF 6和IRE 1 α可以协同调节OA软骨中内源性XBP 1 S基因的表达。更重要的是，通过影响caspase 3、caspase 9、caspase 12、p-JNK 1和CHOP，XBPAS是骨关节炎中细胞凋亡的负调节剂。(C)版权所有© 2013 Elsevier Inc.
As we previously reported, transcription factor XBP1S enhances BMP2-induced chondrocyte differentiation and acts as a positive mediator of chondrocyte hypertrophy. The purpose of this study was to determine (1) whether XBP1S influences ER stress-mediated apoptosis in osteoarthritis (OA); (2) whether ATF6 regulates IRE1/XBP1 signal pathway in OA cartilage; (3) what are the associated molecules affecting apoptosis in osteoarthritis and the molecular events underlying this process. Herein, we examined and found that ER stress-associated molecules were activated in OA patients, specifically XBPIS splice and expression were increased markedly by TNF-alpha and IL-1 beta treatments. Transcription factor ATF6 can specifically bind to the promoter of XBP1 gene and enhance the expression of XBP1S spliced by IRE1 alpha in osteoarthritis cartilage. Furthermore, siXBP1S can enhance ER stress-mediated apoptosis and main matrix degradation in osteoarthritis. Whereas AdXBP1S can inhibit ER stress-mediated apoptosis and TNF alpha induced nitrite production in OA cartilage. In a word, our observations demonstrate the importance of XBP1S in osteoarthritis. ATF6 and IRE1 alpha can regulate endogenous XBP1S gene expression synergistically in OA cartilage. More significantly, XBPIS was a negative regulator of apoptosis in osteoarthritis by affecting caspase 3, caspase 9, caspase 12, p-JNK1, and CHOP. (C) 2013 Elsevier Inc All rights reserved.