title: β-adrenergic receptor signaling regulates Ptgs2 by driving circadian gene expression in osteoblasts.
abstract: The sympathetic nervous system modulates bone remodeling and mediates the expression of core clock genes in part through the β-adrenergic receptor (β-AR) in osteoblasts. In this study, we show that in MC3T3-E1 osteoblastic cells that isoproterenol (Iso), a non-selective β-AR agonist, upregulated the transcriptional factor Nfil3, and induced rhythmic mRNA expression of prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox2). The rhythmic effects of Iso on Ptgs2 expression were mediated by interplay between the Per2 and Bmal1 clock genes in osteoblasts. In addition, Ptgs2 was significantly decreased in bone after continuous Iso treatment. Overexpression of Nfil3 decreased Ptgs2 expression in MC3T3-E1 cells. Knockdown of Nfil3 upregulated the expression of Ptgs2 in MC3TC-E1 cells, indicating that Nfil3 negatively regulated Ptgs2 in osteoblasts. Furthermore, Iso acutely induced the expression Nfil3 and increased the binding of Nfil3 to the Ptgs2 promoter in MC3T3-E1 cells. These results suggest that Iso-mediated induction of Nfil3 in osteoblasts regulates the expression of Ptgs2 by driving the expression of circadian clock genes. These findings provide new evidence for a physiological role of circadian clockwork in bone metabolism.
authors.affiliation: Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, Nagoya 464-8650, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Hirai
authors.affiliation: Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, Nagoya 464-8650, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, Nagoya 464-8650, Japan togariaf@dpc.agu.ac.jp.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Togari
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D056926:CLOCK Proteins / Q000378:metabolism*; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C497441:Nfil3 protein, mouse; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D014157:Transcription Factors; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: Clock gene; Cox2; Nfil3; Osteoblast; Ptgs2; β-adrenergic receptor