BMAL1 regulates osteoblast differentiation through mTOR/GSK3β/β-catenin pathway

in Journal of Molecular Endocrinology
Authors:
Huixia LiDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China

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Hui MengDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China

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Min XuDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China

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Xin GaoDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China

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Xulei SunDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China

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Xinxin JinDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China

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Hongzhi SunDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China

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Correspondence should be addressed to H Sun: sunhongzhi@mail.xjtu.edu.cn
DOI:
https://doi.org/10.1530/JME-22-0181
Volume/Issue:
Volume 70: Issue 4
Article Type:
Research Article
Article ID:
e220181
Online Publication Date:
19 Apr 2023
Copyright:
© the author(s) 2023
Restricted access

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Bone mass declines with age and its maintenance is tightly linked to osteoblasts (crucial bone-building cells). Although disruption of the peripheral circadian clock is involved in various pathologies including aging-related diseases, evidence regarding how the peripheral clock regulates bone mass remains elusive. In the present study, we aimed to elucidate the effects of Bmal1 (the key activator of the peripheral circadian clock system) knockdown by lentivirus-mediated shRNA on osteoblast differentiation and its related mechanisms. We found that the expression of osteogenic markers, alkaline phosphatase activity, and mineralization were decreased, whereas apoptosis and inflammatory response were increased in Bmal1 knockdown osteoblasts. In addition, Bmal1 knockdown promoted ERK and JNK phosphorylation, as well as mTOR activity, whereas mTOR inhibition by rapamycin abrogated Bmal1 knockdown-mediated effects on osteoblast differentiation and mineralization capacity. Remarkably, Bmal1 knockdown in osteoblasts inhibited GSK3β/β-catenin signaling with decreased β-catenin expression and GSK-3β phosphorylation at serine 9, while GSK3β inhibition with TDZD-8, but not WNT3a or SKL2001, rescued Bmal1 knockdown-induced defects in osteoblast differentiation. Moreover, rapamycin partly nullified the suppression of Bmal1 knockdown on β-catenin expression and GSK-3β phosphorylation. Collectively, overall data indicated that circadian gene Bmal1 regulated osteoblast differentiation and inflammatory response in an mTOR/GSK3β/β-catenin-dependent manner, and thereby may contribute to the mineralization process and bone modeling/remodeling.

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Print ISSN:
0952-5041
Online ISSN:
1479-6813
Copyright:
© the author(s) 2023
Article ID:
e220181
Article Type:
Research Article
Received Date:
21 Feb 2023
Accepted Date:
14 Mar 2023
Print Publication Date:
01 May 2023
Online Publication Date:
19 Apr 2023
Keywords:
BMAL1; osteoblast differentiation; mTOR; GSK3β/β-catenin

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