Intestinal clock system regulates skeletal homeostasis.

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.