Wang Dong, Peng Pandi, Dudek Michal, Hu Xueyu, Xu Xiaolong, Shang Qiliang, Wang Di, Jia Haoruo, Wang Han, Gao Bo, Zheng Chao, Mao Jianxin, Gao Chu, He Xin, Cheng Pengzhen, Wang Huanbo, Zheng Jianmin, Hoyland Judith A, Meng Qing-Jun, Luo Zhuojing, Yang Liu
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.
Bone Res. 2022 Feb 25;10(1):20. doi: 10.1038/s41413-022-00187-z.
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.
昼夜节律时钟参与维持包括椎间盘（IVD）在内的外周组织的内环境稳定。异常机械负荷是椎间盘退变（IDD）的已知危险因素。基于日常休息和活动的有节奏负荷模式，我们推测异常机械负荷可能会抑制IVD时钟，导致IDD。在此，我们研究了异常负荷对IVD时钟的影响，并旨在通过靶向核心时钟分子脑和肌肉芳香烃受体核转运蛋白样蛋白1（BMAL1）来抑制压缩诱导的IDD。在本研究中，我们发现BMAL1基因敲除小鼠表现出与人类IDD相似的影像学特征，并且通过对149个人类IVD样本的系统分析，BMAL1表达与IDD严重程度呈负相关。IVD中的内在昼夜节律时钟因过度负荷而受到抑制，慢病毒介导的BMAL1过表达减轻了压缩诱导的IDD。Y-27632或褪黑素对RhoA/ROCK通路的抑制减弱了压缩诱导的BMAL1表达降低。最后，这两种药物在昼夜压缩模型中部分恢复了BMAL1表达并减轻了IDD。我们的结果首次表明，过度负荷通过RhoA/ROCK通路抑制髓核组织的昼夜节律时钟，抑制该通路可能通过保留BMAL1表达来预防压缩诱导的IDD。这些发现强调了昼夜节律时钟对IVD内环境稳定的重要性，并为IDD提供了一种潜在有效的治疗策略。
