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中华口腔医学研究杂志(电子版) ›› 2024, Vol. 18 ›› Issue (04) : 211 -218. doi: 10.3877/cma.j.issn.1674-1366.2024.04.001

青年编委专栏

内质网应激介导的牙周炎骨改建失衡的研究进展
孙鸿坤1, 艾虹1, 陈正1,†()   
  1. 1. 中山大学附属第三医院口腔医学中心，广州　510630
  • 收稿日期:2024-03-12 出版日期:2024-08-01
  • 通信作者: 陈正

Advances in endoplasmic reticulum stress-mediated bone remodeling imbalance in periodontitis

Hongkun Sun1, Hong Ai1, Zheng Chen1,†()   

  1. 1. Center of Stomatology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
  • Received:2024-03-12 Published:2024-08-01
  • Corresponding author: Zheng Chen
  • Supported by:
    National Natural Science Foundation of China(82271021); Science and Technology Planning Project of Guangzhou(2024A03J0098); Sun Yat-sen University Basic Scientific Research Business Fund for Young Teachers Training Project(23qnpy143)
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孙鸿坤, 艾虹, 陈正. 内质网应激介导的牙周炎骨改建失衡的研究进展[J]. 中华口腔医学研究杂志(电子版), 2024, 18(04): 211-218.

Hongkun Sun, Hong Ai, Zheng Chen. Advances in endoplasmic reticulum stress-mediated bone remodeling imbalance in periodontitis[J]. Chinese Journal of Stomatological Research(Electronic Edition), 2024, 18(04): 211-218.

牙周炎是以牙周组织破坏为特征的慢性感染性疾病，宿主的免疫反应是导致附着丧失、牙槽骨吸收的重要原因。蛋白合成负荷过重时，易产生未折叠或错误折叠蛋白，其在内质网内腔积聚后产生内质网应激（ERS）。虽然细胞可以通过相关通路诱发非折叠蛋白应答反应（UPR）缓解ERS，但在牙周炎病理环境下，ERS不可避免地持续存在，而与之互作的UPR会介导促炎转录程序并诱发细胞凋亡，导致骨改建失衡、牙槽骨质丢失。本文就ERS介导的牙周炎骨改建失衡及其潜在治疗靶点相关研究进行回顾，以进一步了解ERS在牙周炎骨代谢及治疗中的作用和意义。

关键词: 牙周炎, 内质网应激, 非折叠蛋白应答, 细胞凋亡, 牙槽骨质丢失

Periodontitis is a chronic infectious disease characterized by the destruction of periodontal tissue. The host's immune response is an important cause of attachment loss and alveolar bone resorption. When protein synthesis is overloaded, it is easy to produce unfolded or misfolded proteins which accumulate in the endoplasmic reticulum lumen and cause endoplasmic reticulum stress (ERS). Although the cells can induce an unfolded protein response (UPR) to mitigate ERS through related pathways, ERS inevitably persists in the pathological environment of periodontitis, and the interacting UPR can mediate pro-inflammatory transcriptional procedures and induce apoptosis, leading to the imbalance of bone remodeling and alveolar bone loss. This article reviewed the studies on ERS mediated bone remodeling imbalance in periodontitis and its potential therapeutic targets in order to further understand the role and significance of ERS in bone metabolism and treatment of periodontitis.

Key words: Periodontitis, Endoplasmic reticulum stress, Unfolded protein response, Apoptosis, Alveolar bone loss
图1 内质网应激（ERS）通过非折叠蛋白应答反应（UPR）的代偿途径　肌醇必需酶1α（IRE1α）-X盒结合蛋白1（XBP1）通路：XBP1的mRNA被IRE1α激活的核酸内切酶剪切为X盒结合蛋白1剪接体（XBP1s）后，进入细胞核，与内质网应激反应元件（ERSE）结合，启动UPR；内质网膜蛋白激酶（PERK）-真核生物起始因子2的α亚基（eIF2α）通路：磷酸化的PERK促进eIF2α磷酸化，磷酸化eIF2α能够暂时抑制蛋白合成和新合成蛋白流入内质网，以缓解ERS[13]；活化转录因子6（ATF6）通路：ATF6通过高尔基体定位信号转移至高尔基体中，被位点1蛋白酶（S1P）和位点2蛋白酶（S2P）剪切，剪切成的片段进入胞核结合ERSE，启动UPR靶基因的转录[17]，本图由Figdraw绘制。
图2 持续的内质网应激（ERS）经非折叠蛋白应答反应（UPR）通路介导的骨改建失衡　肌醇必需酶1α（IRE1α）-X盒结合蛋白1（XBP1）通路：活化IRE-1α与TNF受体相关因子2（TRAF2）结合后激活细胞凋亡信号调节激酶1（ASK1），三者形成复合物后激活c-Jun氨基末端蛋白激酶（JNK）信号通路，介导细胞凋亡[29]；内质网膜蛋白激酶（PERK）-真核生物起始因子2的α亚基（eIF2α）通路中：持续活化的PERK通过促进转录激活因子4（ATF4）mRNA的表达，上调CCAAT增强子结合蛋白同源蛋白（CHOP）基因，表达关键凋亡因子CHOP，其使eIF2α去磷酸化，致该通路代偿失效，加剧内质网应激（ERS），形成恶性循环，进而诱导细胞凋亡。CHOP可通过激活内质网氧化还原酶-1α改变内质网氧化还原状态，上调活性氧水平（ROS），触发Ca2+释放，诱导细胞凋亡[15]；活化转录因子6（ATF6）通路：持续表达的X盒结合蛋白1剪接体（XBP1s）将促进NF-κB受体激活蛋白配体（RANKL）的表达，RANKL激活内质网膜上cAMP应答元件结合蛋白H（CREBH），使其进入胞核，促进活化T细胞核因子1蛋白（NFACT1）的表达，进而促进破骨细胞的分化[36,37]，本图由Figdraw绘制。
表1 抑制间充质干细胞内质网应激（ERS）水平的调控靶点
靶点 涉及通路 上调/下调 机制
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METTL3 - 下调 诱导OC凋亡[45]
CircCDK8 - 上调 抑制PDLSC成骨分化[47]
XBP1 IRE1α 上调 促进PDLSC成骨能力[31]
TNF-α JNK、PERK 上调 抑制BMSC和PDLSC的成骨分化[48,49]
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