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Intestinal clock system regulates skeletal homeostasis
Masanobu Kawai, … , Keiichi Ozono, Toshimi Michigami
Masanobu Kawai, … , Keiichi Ozono, Toshimi Michigami
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(5):e121798. https://doi.org/10.1172/jci.insight.121798.
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Research Article Bone biology Gastroenterology

Intestinal clock system regulates skeletal homeostasis

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Abstract

The circadian clock network is an evolutionarily conserved system involved in the regulation of metabolic homeostasis; however, its impacts on skeletal metabolism remain largely unknown. We herein demonstrated that the circadian clock network in the intestines plays pivotal roles in skeletal metabolism such that the lack of the Bmal1 gene in the intestines (Bmal1Int–/– mice) caused bone loss, with bone resorption being activated and bone formation suppressed. Mechanistically, Clock protein interaction with the vitamin D receptor (VDR) accelerated its binding to the VDR response element by enhancing histone acetylation in a circadian-dependent manner, and this was lost in Bmal1Int–/– mice because nuclear translocation of Clock required the presence of Bmal1. Accordingly, the rhythmic expression of VDR target genes involved in transcellular calcium (Ca) absorption was created, and this was not observed in Bmal1Int–/– mice. As a result, transcellular Ca absorption was impaired and bone resorption was activated in Bmal1Int–/– mice. Additionally, sympathetic tone, the activation of which suppresses bone formation, was elevated through afferent vagal nerves in Bmal1Int–/– mice, the blockade of which partially recovered bone loss by increasing bone formation and suppressing bone resorption in Bmal1Int–/– mice. These results demonstrate that the intestinal circadian system regulates skeletal bone homeostasis.

Authors

Masanobu Kawai, Saori Kinoshita, Miwa Yamazaki, Keiko Yamamoto, Clifford J. Rosen, Shigeki Shimba, Keiichi Ozono, Toshimi Michigami

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Figure 1

Rhythmic recruitment of VDR at the VDR target genes disappears in Bmal1Int–/– mice.

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Rhythmic recruitment of VDR at the VDR target genes disappears in Bmal1I...
(A) Villi were collected from the duodenum at 8 weeks of age every 4 hours, and expression of clock genes of interest was determined by real-time RT-PCR (n = 3). (B) Wheel-running activity was recorded and actograms were double plotted. No differences were observed between Bmal1Intfl/fl and Bmal1Int–/– mice. Shaded area represents dark phase. LD, 12-hour light/12-hour dark cycle; DD, constant darkness. A representative of at least 3 independent experiments is shown. (C) Villi were collected from the duodenum at 8 weeks of age every 4 hours, and expression of genes involved in transcellular Ca transport was determined by real-time RT-PCR (n = 6). Trpv6 (a): P < 0.05, ZT8 vs. ZT0; P < 0.01, ZT8 vs. ZT12 and ZT16; P < 0.001, ZT8 vs. ZT4 and ZT20; in Bmal1Intfl/fl mice, by 1-way ANOVA. Trpv6 (b): P < 0.05, ZT12 vs. ZT0, ZT4, and ZT16; P < 0.01, ZT12 vs. ZT20; in Bmal1Int–/– mice, by 1-way ANOVA. Cabp9k (a): P < 0.05, ZT8 vs. ZT0; P < 0.01, ZT8 vs. ZT4, ZT12, ZT16, and ZT20; in Bmal1Intfl/fl mice, by 1-way ANOVA. Cabp9k (b): P < 0.05, ZT12 vs. ZT0 and ZT4; P < 0.01, ZT12 vs. ZT20; in Bmal1Int–/– mice, by 1-way ANOVA. Pmca1b (a): P < 0.05, ZT8 vs. ZT20; P < 0.01, ZT8 vs. ZT0, ZT4 and ZT12; P < 0.001, ZT8 vs. ZT20; in Bmal1Intfl/fl mice, by 1-way ANOVA. Pmca1b (b): P < 0.05, ZT12 vs. ZT16 and ZT20; in Bmal1Int–/– mice, by 1-way ANOVA. *P < 0.05; Bmal1Intfl/fl vs. Bmal1Int–/– mice at ZT8 by Student’s t test. (D) Recruitment of VDR at the VDRE of Cyp24a1 and Trpv6 genes was analyzed 1 and 4 hours after 1,25-(OH)2D3 (VD) injection by ChIP assay (n = 3–5). Rhythmic pattern of VDR recruitment in Bmal1Intfl/fl mice was not detected in Bmal1Int–/– mice. *P < 0.001, **P < 0.01, ***P < 0.05 by 1-way ANOVA.
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