title: Bone Resorption Is Regulated by Circadian Clock in Osteoblasts.
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. © 2017 American Society for Bone and Mineral Research.
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.|Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takarada
authors.affiliation: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ochi
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Nakazato
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamada
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kodama
authors.affiliation: Department of Health Science, College of Pharmacy, Nihon University, Chiba, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shimba
authors.affiliation: Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mieda
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Fukasawa
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Kakeru
authors.initials: K
authors.lastname: Ozaki
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iezaki
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujikawa
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yoneda
authors.affiliation: Department of Environmental and Life Sciences, and Electronics-Inspired Interdisciplinary Research Institute (EIIRIS), Toyohashi University of Technology, Toyohashi, Aichi, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Numano
authors.affiliation: Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hida
authors.affiliation: Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Tei
authors.affiliation: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
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*; D002478:Cells, Cultured; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism*; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D056950:Period Circadian Proteins; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: BONE RESORPTION; CLOCK; OSTEOBLASTS; RANKL