Regulation of Clock Genes by Adrenergic Receptor Signaling in Osteoblasts
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ORIGINAL PAPER
Regulation of Clock Genes by Adrenergic Receptor Signaling in Osteoblasts Takao Hirai1
Received: 25 April 2017 / Revised: 19 July 2017 / Accepted: 24 July 2017 © Springer Science+Business Media, LLC 2017
Abstract The clock system has been identified as one of the major mechanisms controlling cellular functions. Circadian clock gene oscillations also actively participate in the functions of various cell types including bone-related cells. Previous studies demonstrated that clock genes were expressed in bone tissue and also that their expression exhibited circadian rhythmicity. Recent findings have shown that sympathetic tone plays a central role in biological oscillations in bone. Adrenergic receptor (AR) signaling regulates the expression of clock genes in cancellous bone. Furthermore, α1-AR signaling in osteoblasts is known to negatively regulate the expression of bone morphogenetic protein-4 (Bmp4) by up-regulating nuclear factor IL-3 (Nfil3)/e4 promoter-binding protein 4 (E4BP4). The ablation of α1B-AR signaling also increases the expression of the Bmp4 gene in bone. The findings of transient overexpression and siRNA experiments have supported the involvement of the transcription factor CCAAT/enhancerbinding protein delta (C/EBPδ, Cebpd) in Nfil3 and Bmp4 expression in MC3T3-E1 cells. These findings suggest that the effects of Cebpd are due to the circadian regulation of Bmp4 expression, at least in part, by the up-regulated expression of the clock gene Nfil3 in response to α1B-AR signaling in osteoblasts. Therefore, AR signaling appears to modulate cellular functionality through the expression of clock genes that are circadian rhythm regulators in osteoblasts. The expression of clock genes regulated by
* Takao Hirai t‑[email protected] 1
Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1‑100 Kusumoto‑cho, Chikusa‑ku, Nagoya 464‑8650, Japan
the sympathetic nervous system and clock-controlled genes that affect bone metabolism are described herein. Keywords Adrenergic receptor · Bmp4 · Clock genes · Bone remodeling · Osteoblast Abbreviations AR Adrenergic receptor BMAL1 Brain and muscle arnt-like protein 1 BMP4 Bone morphogenetic protein-4 CEBPD CCAAT/enhancer-binding protein delta CLOCK Circadian locomotor output cycles kaput CRY Cryptochromes E4BP4 E4 promoter-binding protein 4 M-CSF Macrophage colony-stimulating factor NFATc1 Nuclear factor of activated T cells cytoplasmic 1 Nfil3 Nuclear factor IL-3 PER Period PHE Phenylephrine RANKL Receptor activator of nuclear factor kappa-B ligand SCN Suprachiasmatic nucleus TRAP Tartrate-resistant acid phosphatase ZT Zeitgeber time
Introduction The circadian clock controls important mammalian circadian rhythms [1–4]. The main circadian rhythm is regulated by the central clock in the suprachiasmatic nucleus (SCN), which is located in the hypothalamus and is regarded as the master circadian pacemaker that controls most of the physical circadian rhythms in mammals. Circadian rhythms
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