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Circadian rhythm modulates endochondral bone formation via MTR1/AMPKβ1/BMAL1 signaling axis.

ABSTRACT: The circadian clock is a master regulator in coordinating daily oscillations of physiology and behaviors. Nevertheless, how the circadian rhythm affects endochondral ossification is poorly understood. Here we showed that endochondral bone formation exhibits circadian rhythms, manifested as fast DNA replication in the daytime, active cell mitosis, and matrix synthesis at night. Circadian rhythm disruption led to endochondral ossification deformities. The mechanistic dissection revealed that melatonin receptor 1 (MTR1) periodically activates the AMPKβ1 phosphorylation, which then orchestrates the rhythms of cell proliferation and matrix synthesis via destabilizing the clock component CRY1 and triggering BMAL1 expression. Accordingly, the AMPKβ1 agonist is capable of alleviating the abnormity of endochondral ossification caused by circadian dysrhythmias. Taken together, these findings indicated that the central circadian clock could control endochondral bone formation via the MTR1/AMPKβ1/BMAL1 signaling axis in chondrocytes. Also, our results suggested that the AMPKβ1 signaling activators are promising medications toward endochondral ossification deformities.

SUBMITTER: Yu S

PROVIDER: S-EPMC8991200 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Circadian rhythm modulates endochondral bone formation via MTR1/AMPKβ1/BMAL1 signaling axis.

Yu Shaoling S Tang Qingming Q Chen Guangjin G Lu Xiaofeng X Yin Ying Y Xie Mengru M Long Yanlin Y Zheng Wenhao W Guo Fengyuan F Shao Longquan L Shi Anbing A Chen Lili L

Cell death and differentiation 20220129 4

The circadian clock is a master regulator in coordinating daily oscillations of physiology and behaviors. Nevertheless, how the circadian rhythm affects endochondral ossification is poorly understood. Here we showed that endochondral bone formation exhibits circadian rhythms, manifested as fast DNA replication in the daytime, active cell mitosis, and matrix synthesis at night. Circadian rhythm disruption led to endochondral ossification deformities. The mechanistic dissection revealed that melat ...[more]

PMID: 35094018

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Project description:Age-related bone loss and disease strongly affect the quality of life of the elderly population. Cellular circadian rhythms have been reported to regulate bone aging, and micro RNAs (miRNAs) play crucial posttranscriptional regulatory roles in the peripheral clock network. Proliferation capability, osteogenic lineage commitment, senescence-associated secreted phenotype (SASP) and circadian oscillation of clock genes under osteogenic condition were assessed in bone marrow mesenchymal stromal cells (BMSCs) from young adult and aged adult mice. miRNAs targeting the core clock gene brain and muscle arntl-like protein 1 (Bmal1) were screened and verified in young and old BMSCs with RT-qPCR and Western Blot analysis. ChIP-seq and RNA-seq datasets were mined to define the downstream mechanism and gain- and loss-of-function genetic experiments were performed to confirm the hypothesis. To compare the therapeutic effect of these clock-engineered BMSCs, SASP and osteogenic capability of Bmal1-overexpressing and miR-142-3p-inhibited BMSCs were investigated in vitro and transplanted into bone defects and femur cavities of aged mice. Aged BMSCs displayed an abolished circadian rhythm, impaired self-renewal capability and decreased osteoblast differentiation. miR-142-3p was elevated with aging, which downregulated Bmal1 and diminished the osteogenic potential of BMSCs. In addition, Bmal1 inhibited YAP expression to promote BMSCs osteogenesis, which was independent from the activation of Hippo signaling pathway. Overexpression of Bmal1 or inhibition of miR-142-3p rescued the molecular temporal rhythm and osteoblast differentiation ex vivo. Cell-based circadian therapy showed improved bone formation and higher turnover levels in vivo. This study demonstrates that transcriptional and post-transcriptional level clock-modified BMSCs rescued circadian oscillation and age-related bone loss via miR-142-3p/Bmal1/YAP signaling axis. These data provide promising clinical prospects of circadian-mediated stromal cell-based therapy and bone tissue regeneration.

Dataset Information

Circadian rhythm modulates endochondral bone formation via MTR1/AMPKβ1/BMAL1 signaling axis.

Publications

Circadian rhythm modulates endochondral bone formation via MTR1/AMPKβ1/BMAL1 signaling axis.

Similar Datasets

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