title: The Circadian Gene Clock Regulates Bone Formation Via PDIA3.
abstract: The expression patterns of clock-controlled genes (ccgs) are regulated by circadian rhythm, which is a major regulatory and physiological mechanism tied to the solar day. Disruptions in circadian rhythm contribute to the development of cardiovascular diseases, cancer, metabolic syndromes, and aging. It has been reported that bone remodeling is also regulated by circadian rhythm. However, the molecular mechanism by which the circadian gene Clock regulates bone remodeling has yet to be elucidated. Here, we show that Clock mutant mice exhibit a significant reduction in bone density as well as increased apoptosis. Protein disulfide isomerase family A member 3 (PDIA3) is a 1,25-dihydroxy-vitamin D3 [1α,25(OH)2D3] receptor that can regulate bone formation and apoptosis. Using luciferase and ChIP assays, we confirmed that Pdia3 is a ccg. Clock activates Pdia3 transcription by binding the E-box promoter, and transcription is decreased in ClockΔ19mutant mice. Forced expression of Pdia3 or of Clock completely rescues the osteogenic disorders found in the mutant background and inhibits apoptosis in vivo and in vitro. Furthermore, ablation of PDIA3 via RNA interference completely blocks the compensatory effect of forced expression of Clock in osteoblasts. Our results demonstrate that the core circadian gene Clock regulates bone formation via transcriptional control of 1,2,5(OH)2D3 receptor PDIA3. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|Research Center on Aging and Medicine, Fudan University, Shanghai, China.
authors.forename: Gongsheng
authors.initials: G
authors.lastname: Yuan
authors.affiliation: Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Bingxuan
authors.initials: B
authors.lastname: Hua
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Cai
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|Research Center on Aging and Medicine, Fudan University, Shanghai, China.|State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.affiliation: Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Zuoqin
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|Research Center on Aging and Medicine, Fudan University, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|Research Center on Aging and Medicine, Fudan University, Shanghai, China.
authors.forename: Ruizhe
authors.initials: R
authors.lastname: Qian
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D057906:Circadian Clocks / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010012:Osteogenesis / Q000502:physiology*; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*
chemical_list: D056926:CLOCK Proteins; C538944:Clock protein, mouse; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases
keywords: BONE FORMATION; CIRCADIAN LOCOMOTOR OUTPUT CYCLES KAPUT; MINERALIZATION; OSTEOBLASTS; PDIA3