title: Circadian Clock Regulates Bone Resorption in Mice.
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. © 2016 American Society for Bone and Mineral Research.
authors: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.|Department of Orthopedic Surgery and Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Cheng
authors: C
authors: Xu
authors: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
authors: Hiroki
authors: H
authors: Ochi
authors: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
authors: Toru
authors: T
authors: Fukuda
authors: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
authors: Shingo
authors: S
authors: Sato
authors: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
authors: Satoko
authors: S
authors: Sunamura
authors: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Ishikawa, Japan.
authors: Takeshi
authors: T
authors: Takarada
authors: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Ishikawa, Japan.
authors: Eiichi
authors: E
authors: Hinoi
authors: Department of Orthopedic Surgery and Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Okawa
authors: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
authors: Shu
authors: S
authors: Takeda
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism*; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D057906:Circadian Clocks / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D019061:src-Family Kinases
keywords: BMAL1; CIRCADIAN CLOCK; NFATC1; SRCS FAMILY