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J Bone Miner Res. 2017 Apr;32(4):872-881. doi: 10.1002/jbmr.3053. Epub 2017 Mar 3.

Bone Resorption Is Regulated by Circadian Clock in Osteoblasts.

Author information

1
Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
2
Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
3
Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
4
Department of Health Science, College of Pharmacy, Nihon University, Chiba, Japan.
5
Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
6
Department of Environmental and Life Sciences, and Electronics-Inspired Interdisciplinary Research Institute (EIIRIS), Toyohashi University of Technology, Toyohashi, Aichi, Japan.
7
Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
8
Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa, Japan.

Abstract

We have previously shown that endochondral ossification is finely regulated by the Clock system expressed in chondrocytes during postnatal skeletogenesis. Here we show a sophisticated modulation of bone resorption and bone mass by the Clock system through its expression in bone-forming osteoblasts. Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) and Period1 (Per1) were expressed with oscillatory rhythmicity in the bone in vivo, and circadian rhythm was also observed in cultured osteoblasts of Per1::luciferase transgenic mice. Global deletion of murine Bmal1, a core component of the Clock system, led to a low bone mass, associated with increased bone resorption. This phenotype was recapitulated by the deletion of Bmal1 in osteoblasts alone. Co-culture experiments revealed that Bmal1-deficient osteoblasts have a higher ability to support osteoclastogenesis. Moreover, 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ]-induced receptor activator of nuclear factor κB ligand (Rankl) expression was more strongly enhanced in both Bmal1-deficient bone and cultured osteoblasts, whereas overexpression of Bmal1/Clock conversely inhibited it in osteoblasts. These results suggest that bone resorption and bone mass are regulated at a sophisticated level by osteoblastic Clock system through a mechanism relevant to the modulation of 1,25(OH)2 D3 -induced Rankl expression in osteoblasts.

KEYWORDS:

BONE RESORPTION; CLOCK; OSTEOBLASTS; RANKL

PMID:
27925286
DOI:
10.1002/jbmr.3053
[Indexed for MEDLINE]
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