The circadian clock participates in maintaining homeostasis in peripheral tissues,including intervertebral discs(IVDs).Abnormal mechanical loading is a known risk factor for intervertebral disc degeneration(IDD).Based on the rhythmic daily loading pattern of rest and activity,we hypothesized that abnormal mechanical loading could dampen the IVD clock,contributing to IDD.Here,we investigated the effects of abnormal loading on the IVD clock and aimed to inhibit compression-induced IDD by targeting the core clock molecule brain and muscle Arnt-like protein-1(BMAL1).In this study,we showed that BMAL1 KO mice exhibit radiographic features similar to those of human IDD and that BMAL1 expression was negatively correlated with IDD severity by systematic analysis based on 149 human IVD samples.The intrinsic circadian clock in the IVD was dampened by excessive loading,and BMAL1 overexpression by lentivirus attenuated compression-induced IDD.Inhibition of the RhoA/ROCK pathway by Y-27632 or melatonin attenuated the compression-induced decrease in BMAL1 expression.Finally,the two drugs partially restored BMAL1 expression and alleviated IDD in a diurnal compression model.Our results first show that excessive loading dampens the circadian clock of nucleus pulposus tissues via the RhoA/ROCK pathway,the inhibition of which potentially protects against compression-induced IDD by preserving BMAL1 expression.These findings underline the importance of the circadian clock for IVD homeostasis and provide a potentially effective therapeutic strategy for IDD.

Dong Wang;Pandi Peng;Michal Dudek;Xueyu Hu;Xiaolong Xu;Qiliang Shang;Di Wang;Haoruo Jia;Han Wang;Bo Gao;Chao Zheng;Jianxin Mao;Chu Gao;Xin He;Pengzhen Cheng;Huanbo Wang;Jianmin Zheng;Judith A.Hoyland;Qing-Jun Meng;Zhuojing Luo;Liu Yang

Institute of Orthopedic Surgery,Xijing Hospital,Fourth Military Medical University,Xi'an 710032,People's Republic of China;Medical Research Institute,Northwestern Polytechnical University,Xi'an 710068,People's Republic of China;School of Biological Sciences,Faculty of Biology,Medicine and Health,University of Manchester,Manchester M13 9PL,UK;Wellcome Centre for Cell Matrix Research,University of Manchester,Manchester M13 9PL,UK;Department of Medicine Chemistry and Pharmaceutical Analysis,School of Pharmacy,Fourth Military Medical University,Xi'an 710032,People's Republic of China;Radiology Department,Xijing Hospital,Fourth Military Medical University,Xi'an 710032,People's Republic of China

骨研究（英文版）

[1]Dong Wang;Pandi Peng;Michal Dudek;Xueyu Hu;Xiaolong Xu;Qiliang Shang;Di Wang;Haoruo Jia;Han Wang;Bo Gao;Chao Zheng;Jianxin Mao;Chu Gao;Xin He;Pengzhen Cheng;Huanbo Wang;Jianmin Zheng;Judith A.Hoyland;Qing-Jun Meng;Zhuojing Luo;Liu Yang-.Restoring the dampened expression of the core clock molecule BMAL1 protects against compression-induced intervertebral disc degeneration)[J].骨研究（英文版）,2022(02):297-309

IVDs,dampen,dampens

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