Bone Resorption Is Regulated by Circadian Clock in Osteoblasts

Takeshi Takarada, Cheng Xu, Hiroki Ochi, Ryota Nakazato, Daisuke Yamada, Saki Nakamura, Ayumi Kodama, Shigeki Shimba, Michihiro Mieda, Kazuya Fukasawa, Kakeru Ozaki, Takashi Iezaki, Koichi Fujikawa, Yukio Yoneda, Rika Numano, Akiko Hida, Hajime Tei, Shu Takeda, Eiichi Hinoi

Research output: Contribution to journalArticle

29 Citations (Scopus)

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)2D3]-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)2D3-induced Rankl expression in osteoblasts.

Original languageEnglish
Pages (from-to)872-881
Number of pages10
JournalJournal of Bone and Mineral Research
Volume32
Issue number4
DOIs
Publication statusPublished - Apr 2017

Keywords

  • BONE RESORPTION
  • CLOCK
  • OSTEOBLASTS
  • RANKL

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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  • Cite this

    Takarada, T., Xu, C., Ochi, H., Nakazato, R., Yamada, D., Nakamura, S., Kodama, A., Shimba, S., Mieda, M., Fukasawa, K., Ozaki, K., Iezaki, T., Fujikawa, K., Yoneda, Y., Numano, R., Hida, A., Tei, H., Takeda, S., & Hinoi, E. (2017). Bone Resorption Is Regulated by Circadian Clock in Osteoblasts. Journal of Bone and Mineral Research, 32(4), 872-881. https://doi.org/10.1002/jbmr.3053