Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 32, Issue 4, Pages 872-881Publisher
WILEY
DOI: 10.1002/jbmr.3053
Keywords
OSTEOBLASTS; CLOCK; RANKL; BONE RESORPTION
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan [20790250, 26117507, 26460387, 23689004]
- Grants-in-Aid for Scientific Research [26117507, 16H01633, 16H06825, 23689004, 17H04399] Funding Source: KAKEN
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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, 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3]-induced receptor activator of nuclear factor B 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)D-3-induced Rankl expression in osteoblasts. (c) 2017 American Society for Bone and Mineral Research.
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