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Regulation of Clock Genes by Adrenergic Receptor Signaling in Osteoblasts

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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/enhancer-binding 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 the sympathetic nervous system and clock-controlled genes that affect bone metabolism are described herein.

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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

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research to T.H. (16K11495) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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  1. Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan

    Takao Hirai

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Hirai, T. Regulation of Clock Genes by Adrenergic Receptor Signaling in Osteoblasts. Neurochem Res 43, 129–135 (2018). https://doi.org/10.1007/s11064-017-2365-y

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