激素性股骨头缺血坏死中未折叠蛋白反应的作用和机制

The Role of Unfolded Protein Response in Steroid-Induced Avascular Necrosis of the Femoral Head

摘要: 背景：激素性股骨头缺血坏死发病人数逐年递增，发病机制尚不明确，可能与骨细胞的程序性死亡相关，而内质网应激介导的未折叠蛋白反应及其相关信号通路发挥着重要的作用。目的：综述内质网应激、未折叠蛋白反应的相关信号通路，以及二者与细胞程序性死亡之间的关系，总结未折叠蛋白反应的调控机制及与激素性股骨头缺血坏死发病机制相关的研究进展。方法：检索2000至2021年相关文献，以“未折叠蛋白反应，内质网应激，股骨头坏死，糖皮质激素，细胞凋亡，细胞自噬”为中文检索词检索CNKI、万方、维普数据库；以“unfolded protein response, endoplasmic reticulum stress, femur head necrosis, glucocorticoid, cell autophagy, cell apoptosis”为英文检索词检索PubMed、Web of Science数据库。排除重复和较陈旧的文献及Meta分析，最终共55篇文献符合纳入标准。结果与结论：第一，未折叠蛋白反应通过三条信号通路监测并调节内质网中蛋白质折叠的状态，即肌醇需要酶1a、蛋白激酶R样内质网激酶、激活转录因子6途径，在缓解内质网应激和细胞内环境稳态中发挥重要的作用，若刺激过强或持续存在，未折叠蛋白反应维持蛋白质稳态的能力不堪重负，则会诱发细胞程序性死亡。第二，细胞的程序性死亡可能是通过未折叠蛋白反应特定的信号网络而非单一信号通路来调节的。第三，未折叠蛋白反应可能是激素性股骨头缺血坏死发病过程中的重要环节，但具体发病机制仍不明确。

Abstract: Background: The number of steroid-induced avascular necrosis of the femoral head is increasing year by year, and the pathogenesis is not clear, which may be related to the programmed death of bone cells. The unfolded protein response mediated by endoplasmic reticulum stress and its related signaling pathways play an important role effect. Objective: This review summarizes the signal pathways related to endoplasmic reticulum stress, unfolded protein response, and the relationship between the two and programmed cell death, summarizes the regulation mechanism of unfolded protein response and the pathogenesis of hormonal avascular necrosis of the femoral head Research progress. Methods: Relevant articles published from 2000 to 2021 were retrieved from PubMed, Web of Science, CNKI, WanFang, and VIP databases. The keywords were “unfolded protein response, endoplasmic reticulum stress, femur head necrosis, glucocorticoid, cell autophagy, cell apoptosis” in English and Chinese, respectively. The old and duplicate articles were excluded, and 55 articles were included for analysis and discussion. Results and Conclusion: First, the unfolded protein response monitors and regulates the state of protein folding in the endoplasmic reticulum through three signaling pathways. These three pathways are inositol requiring enzyme 1α (IRE1a), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) pathways, which play an important role in relieving endoplasmic reticulum stress and cellular homeostasis. If the stimulus is too strong or persists, the ability of the unfolded protein response to maintain protein homeostasis is overwhelmed, and it will induce programmed cell death. Second, programmed cell death may be regulated by a specific signal network in unfolded protein response rather than a single signal pathway. Third, the unfolded protein response may be an important link in the pathogenesis of steroid-induced avascular necrosis of the femoral head, but the specific pathogenesis is still unclear.