Methionine Enkephalin Suppresses Osteocyte Apoptosis Induced by Compressive Force through Regulation of Nuclear Translocation of NFATc1
Methionine Enkephalin Suppresses Osteocyte Apoptosis Induced by Compressive Force through Regulation of Nuclear Translocation of NFATc1
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蛋氨酸脑啡肽通过调节 NFATc1 核易位抑制压力诱导的骨细胞凋亡
DOI：
10.1002/jbm4.10369
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发表时间：
2020
期刊：
影响因子：
3.8
通讯作者：
Takano‐Yamamoto Teruko
中科院分区：
文献类型：
--
作者：
Sogi Chisumi;Takeshita Nobuo;Jiang Wei;Kim Siyoung;Maeda Toshihiro;Yoshida Michiko;Oyanagi Toshihito;Ito Arata;Kimura Seiji;Seki Daisuke;Takano Ikuko;Sakai Yuichi;Fujiwara Ikuma;Kure Shigeo;Takano‐Yamamoto Teruko
机械应力刺激骨重建，骨重建通过骨形成和再吸收发生，导致响应于机械应力的骨适应。骨细胞感知加载到骨的机械应力，并通过各种细胞过程促进骨重建。骨细胞凋亡被认为是机械应力诱导骨重建过程中骨吸收的细胞过程，但其分子机制尚未完全阐明。最近的研究表明，神经肽在骨代谢中起着至关重要的作用。神经肽甲硫氨酸脑啡肽（MENK）根据细胞类型正性和负性调节细胞凋亡，但MENK在骨细胞凋亡中的作用，随后是骨吸收，响应于机械应力仍然是未知的。本研究旨在探讨MENK在压力诱导骨细胞凋亡中的作用及其机制。我们对小鼠顶骨施加压力，导致骨细胞中MENK表达减少。中和结缔组织生长因子（CTGF）抗体抑制压缩力诱导的MENK减少。MENK给药可抑制压力负荷顶骨中骨细胞凋亡的增加。在顶骨的骨细胞中的NFATc1的核转位被压缩力增强。印加6，抑制NFAT易位到细胞核，抑制骨细胞凋亡的压力加载顶骨的增加。过表达NFATc 1的MLO Y4细胞显示凋亡相关基因的表达增加。MENK给药减少了压缩力加载的顶骨中骨细胞中NFATc1的核转位。此外，MENK抑制Ca2+内流和钙调磷酸酶和钙调蛋白的表达，这是已知的诱导核转位的NFAT在MLO Y4细胞。总之，这项研究表明，骨细胞表达MENK，而MENK的表达通过CTGF信号传导被压缩力抑制。MENK可能通过抑制骨细胞中的Ca 2+信号，从而抑制压力诱导的骨细胞凋亡，继而抑制骨吸收，从而下调NFATc1的核转位。© 2020作者.JBMR Plus由Wiley Periodicals，Inc.出版。美国骨与矿物质研究协会（American Society for Bone and Mineral Research）
Mechanical stress stimulates bone remodeling, which occurs through bone formation and resorption, resulting in bone adaptation in response to the mechanical stress. Osteocytes perceive mechanical stress loaded to bones and promote bone remodeling through various cellular processes. Osteocyte apoptosis is considered a cellular process to induce bone resorption during mechanical stress induced bone remodeling, but the underlying molecular mechanisms are not fully understood. Recent studies have demonstrated that neuropeptides play crucial roles in bone metabolism. The neuropeptide, methionine enkephalin (MENK) regulates apoptosis positively and negatively depending on cell type, but the role of MENK in osteocyte apoptosis, followed by bone resorption, in response to mechanical stress is still unknown. Here, we examined the roles and mechanisms of MENK in osteocyte apoptosis induced by compressive force. We loaded compressive force to mouse parietal bones, resulting in a reduction of MENK expression in osteocytes. A neutralizing connective tissue growth factor (CTGF) antibody inhibited the compressive force induced reduction of MENK. An increase in osteocyte apoptosis in the compressive force loaded parietal bones was inhibited by MENK administration. Nuclear translocation of NFATc1 in osteocytes in the parietal bones was enhanced by compressive force. INCA 6, which inhibits NFAT translocation into nuclei, suppressed the increase in osteocyte apoptosis in the compressive force loaded parietal bones. NFATc1 overexpressing MLO Y4 cells showed increased expression of apoptosis related genes. MENK administration reduced the nuclear translocation of NFATc1 in osteocytes in the compressive force loaded parietal bones. Moreover, MENK suppressed Ca2+influx and calcineurin and calmodulin expression, which are known to induce the nuclear translocation of NFAT in MLO Y4 cells. In summary, this study shows that osteocytes expressed MENK, whereas the MENK expression was suppressed by compressive force via CTGF signaling. MENK downregulated nuclear translocation of NFATc1 probably by suppressing Ca2+signaling in osteocytes and consequently inhibiting compressive force induced osteocyte apoptosis, followed by bone resorption. © 2020 The Authors.JBMR Pluspublished by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.