Yuan Xiaoliang, Liu Haiqing, Li Linfu, Liu Hai, Yang Jianqiong, Shi Weimei, Feng Yuan, Huang Hao, Wu Longhuo
Department of Respiratory Medicine, the First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China.
College of Pharmacy, Gannan Medical University, Ganzhou 341000, China.
Curr Pharm Des. 2017;23(11):1693-1704. doi: 10.2174/1381612822666161025152423.
Endoplasmic reticulum (ER) has evolved an adaptive mechanism called unfolded protein response (UPR) at the initial stage to restore cellular homeostasis. The three ER transmembrane sensors, such as IRE1α, PERK, and ATF6, are the key factors to decide cell fates. They exhibit both advantageous and disadvantageous effects, depending on the micro-environmental state of cells. ER stress has been implicated in chondrocytes proliferation, differentiation, and hypertrophy through regulating transcriptional factors SOX9, Ihh, BMP-2, RUNX, and HIF1/2α. In addition, the chronic ER stress induced by the mutant proteins becomes the pathophysiology of chondrodysplasia. On the other hand, ER stress may induce chondrocytes apoptosis, leading to the degeneration of cartilage. eIF2α-CHOP and JNK activation are the remarkably apoptotic responses to ER stress, while XBP1s and Bip exhibit pro-survival effects. These factors might potentially become therapeutic targets for joint diseases management. This article reviews the pro-survival and pro-apoptotic effects of ER stress as well as their implications in cartilage and chondrocytes.
内质网（ER）在初始阶段进化出一种名为未折叠蛋白反应（UPR）的适应性机制，以恢复细胞内稳态。三种内质网跨膜传感器，如肌醇需求酶1α（IRE1α）、蛋白激酶R样内质网激酶（PERK）和活化转录因子6（ATF6），是决定细胞命运的关键因素。它们根据细胞的微环境状态表现出有利和不利的影响。内质网应激通过调节转录因子性别决定区Y盒9（SOX9）、印度刺猬因子（Ihh）、骨形态发生蛋白2（BMP-2）、 Runt相关转录因子（RUNX）和低氧诱导因子1/2α（HIF1/2α），参与软骨细胞的增殖、分化和肥大。此外，突变蛋白诱导的慢性内质网应激成为软骨发育异常的病理生理学机制。另一方面，内质网应激可能诱导软骨细胞凋亡，导致软骨退变。真核生物翻译起始因子2α（eIF2α）-CCAAT增强子结合蛋白同源蛋白（CHOP）和c-Jun氨基末端激酶（JNK）激活是内质网应激显著的凋亡反应，而X盒结合蛋白1剪接异构体（XBP1s）和结合免疫球蛋白蛋白（Bip）具有促生存作用。这些因素可能成为关节疾病治疗的潜在靶点。本文综述了内质网应激的促生存和促凋亡作用及其在软骨和软骨细胞中的意义。
