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.

Circadian clock—A promising scientific target in oral science

“…Researchers used transgenic mice with a human osteocalcin promoter-related luciferase reporter gene to test the intensity of osteogenic activity at multiple skeletal sites, and the maxillomandibular complex showed the most robust oscillatory pattern at a periodicity of 24 h. Clock gene oscillation shows similarities and different amplitudes during different periods of development; the crests and troughs are close to each other ( Gafni et al, 2009 ). Studies have demonstrated a distinct circadian rhythm in the growth and remodeling of mandibular and condylar cartilage in rats and mice, and the circadian rhythm could modulate endochondral bone formation to promote mandibular development mainly via the MTR1/AMPKβ1/BMAL1 signaling axis ( Yu et al, 2022 ). During the development of the mandible in mice, BMAL1/CLOCK expression levels gradually decrease with increasing age, while the expression levels of PER1/2, REV-ERBα, CRY1/2, and RORα show no obvious change at different developmental stages of mandibular condylar cartilage (MCC) ( Song et al, 2018a ).…”

Dual-Targeted Nanodiscs Revealing the Cross-Talk between Osteogenic Differentiation of Mesenchymal Stem Cells and Macrophages

“…All animal experiments received consent from The Institutional Animal Care and Use Committee at Tongji Medical College, HUST. For BMAL1-deficient mice (Bmal1 –/– , B6.129-Arntltm1Bra/J mice), homozygous mice were produced by breeding heterozygous BMAL1-deficient mating pairs (Bmal1 +/– ) that were kindly provided by Prof. Lili Chen (Wuhan Union Hospital, China) . Mouse tail genotyping was performed with the quick genotyping assay kit for mouse tail (Beyotime, D7283s) according to the manufacturer’s instructions.…”

The role of melatonin in the development of postmenopausal osteoporosis

“…Biorhythm plays an important role in the development of postmenopausal osteoporosis. A recent study showed that the endochondral bone formation process exhibits a biological rhythm characterized by rapid DNA replication and active cellular mitosis during the day, followed by matrix synthesis at night (Yu et al, 2022). The circadian clock regulates the biological cycle of mammalian physiological functions.…”

“…Inactivation of BMAL1 suppressed the differentiation of osteoblasts and enhanced the function of osteoclasts. Melatonin induced AMPKβ1 phosphorylation to increase BMAL1 expression by activating melatonin receptor 1 (Yu et al, 2022). REV-ERB/ROR is a group of response elements that modulate the expression of BMAL1 (Lee et al, 2016).…”