Circadian Clock Regulates Bone Resorption in Mice

Cheng Xu, Hiroki Ochi, Toru Fukuda, Shingo Sato, Satoko Sunamura, Takeshi Takarada, Eiichi Hinoi, Atsushi Okawa, Shu Takeda

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The circadian clock controls many behavioral and physiological processes beyond daily rhythms. Circadian dysfunction increases the risk of cancer, obesity, and cardiovascular and metabolic diseases. Although clinical studies have shown that bone resorption is controlled by circadian rhythm, as indicated by diurnal variations in bone resorption, the molecular mechanism of circadian clock–dependent bone resorption remains unknown. To clarify the role of circadian rhythm in bone resorption, aryl hydrocarbon receptor nuclear translocator-like (Bmal1), a prototype circadian gene, was knocked out specifically in osteoclasts. Osteoclast-specific Bmal1-knockout mice showed a high bone mass phenotype due to reduced osteoclast differentiation. A cell-based assay revealed that BMAL1 upregulated nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (Nfatc1) transcription through its binding to an E-box element located on the Nfatc1 promoter in cooperation with circadian locomotor output cycles kaput (CLOCK), a heterodimer partner of BMAL1. Moreover, steroid receptor coactivator (SRC) family members were shown to interact with and upregulate BMAL1:CLOCK transcriptional activity. Collectively, these data suggest that bone resorption is controlled by osteoclastic BMAL1 through interactions with the SRC family and binding to the Nfatc1 promoter.

Original languageEnglish
Pages (from-to)1344-1355
Number of pages12
JournalJournal of Bone and Mineral Research
Volume31
Issue number7
DOIs
Publication statusPublished - Jul 1 2016
Externally publishedYes

Fingerprint

Circadian Clocks
Bone Resorption
NFATC Transcription Factors
Calcineurin
Osteoclasts
Steroid Receptors
Circadian Rhythm
Aryl Hydrocarbon Receptor Nuclear Translocator
E-Box Elements
Physiological Phenomena
Metabolic Diseases
Knockout Mice
Cardiovascular Diseases
Up-Regulation
Obesity
Bone and Bones
Genes
Neoplasms

Keywords

  • BMAL1
  • CIRCADIAN CLOCK
  • NFATC1
  • SRCS FAMILY

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Xu, C., Ochi, H., Fukuda, T., Sato, S., Sunamura, S., Takarada, T., ... Takeda, S. (2016). Circadian Clock Regulates Bone Resorption in Mice. Journal of Bone and Mineral Research, 31(7), 1344-1355. https://doi.org/10.1002/jbmr.2803

Circadian Clock Regulates Bone Resorption in Mice. / Xu, Cheng; Ochi, Hiroki; Fukuda, Toru; Sato, Shingo; Sunamura, Satoko; Takarada, Takeshi; Hinoi, Eiichi; Okawa, Atsushi; Takeda, Shu.

In: Journal of Bone and Mineral Research, Vol. 31, No. 7, 01.07.2016, p. 1344-1355.

Research output: Contribution to journalArticle

Xu, C, Ochi, H, Fukuda, T, Sato, S, Sunamura, S, Takarada, T, Hinoi, E, Okawa, A & Takeda, S 2016, 'Circadian Clock Regulates Bone Resorption in Mice', Journal of Bone and Mineral Research, vol. 31, no. 7, pp. 1344-1355. https://doi.org/10.1002/jbmr.2803
Xu, Cheng ; Ochi, Hiroki ; Fukuda, Toru ; Sato, Shingo ; Sunamura, Satoko ; Takarada, Takeshi ; Hinoi, Eiichi ; Okawa, Atsushi ; Takeda, Shu. / Circadian Clock Regulates Bone Resorption in Mice. In: Journal of Bone and Mineral Research. 2016 ; Vol. 31, No. 7. pp. 1344-1355.
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