A selective estrogen receptor modulator inhibits tumor necrosis factor-α-induced apoptosis through the ERK1/2 signaling pathway in human chondrocytes
A selective estrogen receptor modulator inhibits tumor necrosis factor-α-induced apoptosis through the ERK1/2 signaling pathway in human chondrocytes
复制标题
DOI：
10.1016/j.bbrc.2012.03.111
复制
发表时间：
2012-05-11
影响因子：
3.1
通讯作者：
Ishiguro, Naoki
中科院分区：
文献类型：
--
作者：
Hattori, Yosuke;Kojima, Toshihisa;Ishiguro, Naoki
肿瘤坏死因子α (tnf - α)是一种介导炎症和细胞死亡活动的多功能性细胞因子，被认为在炎症和退行性关节疾病中诱导软骨细胞软骨溶解。选择性雌激素受体调节剂（SERMs），如雷洛昔芬，通常用于临床环境作为雌激素激动剂或拮抗剂。据推测，雌激素在软骨保护中有潜在的作用；然而，雌激素保护作用的确切分子机制尚不清楚。本研究旨在研究雷洛昔芬是否抑制tnf α诱导的人软骨细胞凋亡，并阐明其机制。我们还研究了雷洛昔芬抗凋亡作用的信号通路。采用DNA片段法和caspase-3活化法检测软骨细胞凋亡。雷洛昔芬显著抑制tnf α诱导的caspase-3激活和软骨细胞DNA断裂水平。雷洛昔芬的抑制作用被雌激素受体拮抗剂ICI 182780所消除。细胞外信号调节激酶1/2 （ERK1/2）调节细胞凋亡，作为凋亡或抗凋亡信号。ERK1/2通路抑制剂PD98059显著增强了tnf - α诱导的细胞凋亡。雷洛昔芬刺激tnf α处理的软骨细胞ERK1/2磷酸化进一步增加。此外，PD98059可抑制雷洛昔芬的抗凋亡作用。此外，雷洛昔芬的抗凋亡作用在ERK1/2 sirna处理的软骨细胞中被完全消除。这些结果表明，雷洛昔芬通过激活雌激素受体和ERK1/2信号通路，阻止tnf - α诱导的人软骨细胞caspase-3依赖性凋亡。(C) 2012爱思唯尔公司版权所有。
Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine mediating inflammatory as well as cell death activities, and is thought to induce chondrocytic chondrolysis in inflammatory and degenerative joint diseases. Selective estrogen receptor modulators (SERMs), such as raloxifene, which are commonly used in clinical settings act as estrogen agonists or antagonists. It is assumed that estrogens have a potential role in cartilage protection; however, the precise molecular mechanism for the protective effects of estrogens is unclear. This study was designed to examine whether raloxifene inhibits TNF-alpha-induced apoptosis in human chondrocytes and to clarify the mechanisms involved. We also investigated the signaling pathways responsible for the anti-apoptotic effect of raloxifene. Apoptosis in chondrocytes was determined by DNA fragmentation assay and caspase-3 activation. Raloxifene significantly inhibited TNF-alpha-induced caspase-3 activation and cell DNA fragmentation levels in chondrocytes. The inhibitory effect of raloxifene was abolished by the estrogen receptor antagonist ICI 182,780. Extracellular signal-regulated kinase 1/2 (ERK1/2) regulates apoptosis, acting as an apoptotic or anti-apoptotic signal. TNF-alpha-induced apoptosis was significantly enhanced by the ERK1/2 pathway inhibitor PD98059. Raloxifene stimulated a further increase in ERK1/2 phosphorylation in TNF-alpha-treated chondrocytes. Furthermore, the anti-apoptotic effects of raloxifene were inhibited by PD98059. In addition, the anti-apoptotic effects of raloxifene were completely abolished in ERK1/2 siRNA-treated chondrocytes. These results suggest that raloxifene prevents caspase-3-dependent apoptosis induced by TNF-alpha in human chondrocytes by activating estrogen receptors and the ERK1/2 signaling pathway. (C) 2012 Elsevier Inc. All rights reserved.