摘要：

骨骼系统的结构完整性依赖于细胞外基质蛋白网络，其合成与质量控制由内质网（endoplasmic reticulum，ER）通过未折叠蛋白反应（unfolded protein response，UPR）精确调控。UPR通过肌醇需求酶1α（inositol-requiring enzyme 1α，IRE1α）-X盒结合蛋白1（X-box binding protein 1，XBP1）、蛋白激酶R样内质网激酶（protein kinase R-like ER kinase，PERK）-真核翻译起始因子2α亚基 （eukaryotic initiation factor 2α subunit，eIF2α） -激活转录因子4 （activating transcription factor 4，ATF4）、激活转录因子6（activating transcription factor 6，ATF6） 3条经典信号通路，动态平衡蛋白质稳态与细胞命运。在生理状态下，PERK-eIF2α-ATF4通路促进成骨细胞胶原合成，IRE1α-XBP1通路调控破骨细胞骨吸收，ATF6介导骨细胞力学响应[如硬骨素（sclerostin，SOST）分泌]；而慢性内质网应激（endoplasmic reticulum stress，ERS）则触发C/EBP同源蛋白（C/EBP homologous protein，CHOP）/c-Jun N端激酶(c-Jun N-terminal kinase，JNK)依赖性细胞凋亡，破坏骨稳态，导致骨质疏松症等疾病。本文系统综述了UPR在骨代谢中的多维调控机制，为靶向治疗提供新策略。

关键词: 内质网未折叠蛋白反应, 骨代谢, 内质网应激, 成骨细胞, 破骨细胞

Abstract:

The structural integrity of the skeletal system depends on the extracellular matrix protein network, whose synthesis and quality control are precisely regulated by the endoplasmic reticulum (ER) through the unfolded protein response (UPR). The UPR dynamically coordinates proteostasis and cell fate through three canonical signaling pathways: Inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1), protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α subunit（eIF2α）-activating transcription factor 4 (ATF4), and activating transcription factor 6 (ATF6). Under physiological conditions, the PERK-eIF2α-ATF4 pathway promotes collagen synthesis in osteoblasts, the IRE1α-XBP1 pathway regulates bone resorption by osteoclasts, and ATF6 mediates the mechanosensory response of osteocytes, such as sclerostin (SOST) secretion. In contrast, chronic endoplasmic reticulum stress (ERS) triggers C/EBP homologous protein（CHOP）/c-Jun N-terminal kinase (JNK)-dependent apoptosis, disrupts bone homeostasis, and contributes to the development of skeletal disorders such as osteoporosis. This review systematically summarizes the multidimensional regulatory mechanisms of the UPR in bone metabolism and provides new strategies for targeted therapy.

Key words: endoplasmic reticulum unfolded protein response, bone metabolism, endoplasmic reticulum stress, osteoblasts, osteoclasts