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Postnatal Conditional Deletion of Bmal1 in Osteoblasts Enhances Trabecular Bone Formation Via Increased BMP2 Signals.
Journal of Bone and Mineral Research ( IF 6.2 ) Pub Date : 2020-03-25 , DOI: 10.1002/jbmr.4017
Zhuang Qian 1 , Ying Zhang 1 , Xiaomin Kang 1 , Huixia Li 2 , Yan Zhang 1 , Xinxin Jin 1 , Xin Gao 2 , Mao Xu 1 , Zhengmin Ma 2 , Liting Zhao 1 , Zhuanmin Zhang 2 , Hongzhi Sun 2 , Shufang Wu 1
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A large number of studies in recent years indicated the involvement of peripheral circadian clock in varied pathologies. However, evidence regarding how peripheral clocks regulate bone metabolism is still very limited. The present study aimed to investigate the direct role of Bmal1 (the key activator of peripheral circadian clock system) in vivo during bone developmental and remodeling stages using inducible osteoblast‐specific Bmal1 knockout mice. Unexpectedly, the removal of Bmal1 in osteoblasts caused multiple abnormalities of bone metabolism, including a progressive increase in trabecular bone mass in as early as 8 weeks, manifested by an 82.3% increase in bone mineral density and 2.8‐fold increase in bone volume per tissue volume. As mice age, an increase in trabecular bone mass persists while cortical bone mass decreases by about 33.7%, concomitant with kyphoscoliosis and malformed intervertebral disk. The increased trabecular bone mass is attributed to increased osteoblast number and osteoblast activity coupled with decreased osteoclastogenesis. Remarkably, the ablation of Bmal1 in osteoblasts promoted the expression level of Bmp2 and phosphorylation of SMAD1, whereas the attenuation of BMP2/SMAD1 signaling partially alleviated the effects of Bmal1 deficiency on osteoblast differentiation and activity. The results revealed that Bmal1 was a transcriptional silencer of Bmp2 by targeting the Bmp2 promoter. The peripheral clock gene Bmal1 in osteoblasts was crucial to coordinate differential effects on trabecular and cortical bones through regulating BMP2/SMAD1 during bone development, thus providing novel insights into a key role of osteoblast Bmal1 in homeostasis and integrity of adult bones. © 2020 American Society for Bone and Mineral Research.

中文翻译:

产后成骨细胞中Bmal1的条件性删除通过增加的BMP2信号增强小梁骨形成。

近年来的大量研究表明,外周昼夜节律钟涉及多种病理。然而,关于外围时钟如何调节骨代谢的证据仍然非常有限。本研究旨在研究Bmal1(外周生物钟系统的关键激活剂)在体内的发育过程中的直接作用,该过程使用可诱导的成骨细胞特异性Bmal1基因敲除小鼠进行。出乎意料的是,删除了Bmal1成骨细胞中的s引起骨代谢的多种异常,包括早在8周骨小梁骨量逐渐增加,表现为骨矿物质密度增加了82.3%,每组织体积的骨量增加了2.8倍。随着小鼠年龄的增长,小梁骨量持续增加,而皮质骨量减少约33.7%,并伴有脊柱后凸畸形和椎间盘畸形。小梁骨量增加归因于成骨细胞数量和成骨细胞活性增加以及破骨细胞生成减少。值得注意的是,Bmal1在成骨细胞中的消融促进了Bmp2的表达水平和SMAD1的磷酸化,而BMP2 / SMAD1信号的减弱部分缓解了Bmal2的作用。Bmal1缺乏对成骨细胞的分化和活性。结果显示,Bmal1通过靶向Bmp2启动子而成为Bmp2的转录沉默子。成骨细胞中的外周时钟基因Bmal1对于在骨发育过程中通过调节BMP2 / SMAD1来协调小梁和皮层骨的差异作用至关重要,从而为成骨细胞Bmal1在体内稳态和成年骨骼完整性中的关键作用提供了新颖的见解。©2020美国骨骼和矿物质研究学会。
更新日期:2020-03-25
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