Circadian Clock Regulates Bone Resorption in Mice
Circadian Clock Regulates Bone Resorption in Mice
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DOI：
10.1002/jbmr.2803
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发表时间：
2016-07
影响因子：
6.2
通讯作者：
Cheng Xu;H. Ochi;T. Fukuda;Shingo Sato;Satoko Sunamura;T. Takarada;E. Hinoi;A. Okawa;S. Takeda-S.-Ta
中科院分区：
文献类型：
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作者：
Cheng Xu;H. Ochi;T. Fukuda;Shingo Sato;Satoko Sunamura;T. Takarada;E. Hinoi;A. Okawa;S. Takeda-S.-Ta
生物钟控制着日常节奏之外的许多行为和生理过程。昼夜节律紊乱会增加患癌症、肥胖症、心血管疾病和代谢疾病的风险。尽管临床研究表明骨吸收受昼夜节律控制，如骨吸收的昼夜变化所示，但昼夜节律依赖性骨吸收的分子机制仍不清楚。为了阐明昼夜节律在骨吸收中的作用，在破骨细胞中特异性敲除了芳香烃受体核转运子样（Bmal 1），一种原型昼夜节律基因。破骨细胞特异性Bmal1基因敲除小鼠由于破骨细胞分化减少而表现出高骨量表型。一项基于细胞的测定显示，BMAL 1通过与位于Nfatc 1启动子上的E盒元件结合，与昼夜节律运动输出周期kaput（CLOCK）（BMAL 1的异源二聚体伴侣）合作，上调活化T细胞的核因子、细胞质钙调磷酸酶依赖性1（Nfatc 1）转录。此外，类固醇受体辅激活因子（SRC）家族成员显示与BMAL1：CLOCK转录活性相互作用并上调。总的来说，这些数据表明骨吸收是由骨细胞BMAL1通过与SRC家族的相互作用和与Nfatc1启动子的结合来控制的。© 2016美国骨与矿物质研究学会。
The circadian clock controls many behavioral and physiological processes beyond daily rhythms. Circadian dysfunction increases the risk of cancer, obesity, and cardiovascular and metabolic diseases. Although clinical studies have shown that bone resorption is controlled by circadian rhythm, as indicated by diurnal variations in bone resorption, the molecular mechanism of circadian clock–dependent bone resorption remains unknown. To clarify the role of circadian rhythm in bone resorption, aryl hydrocarbon receptor nuclear translocator‐like (Bmal1), a prototype circadian gene, was knocked out specifically in osteoclasts. Osteoclast‐specific Bmal1‐knockout mice showed a high bone mass phenotype due to reduced osteoclast differentiation. A cell‐based assay revealed that BMAL1 upregulated nuclear factor of activated T cells, cytoplasmic, calcineurin‐dependent 1 (Nfatc1) transcription through its binding to an E‐box element located on the Nfatc1 promoter in cooperation with circadian locomotor output cycles kaput (CLOCK), a heterodimer partner of BMAL1. Moreover, steroid receptor coactivator (SRC) family members were shown to interact with and upregulate BMAL1:CLOCK transcriptional activity. Collectively, these data suggest that bone resorption is controlled by osteoclastic BMAL1 through interactions with the SRC family and binding to the Nfatc1 promoter. © 2016 American Society for Bone and Mineral Research.