Bone Resorption Is Regulated by Circadian Clock in Osteoblasts

J Bone Miner Res. 2017 Apr;32(4):872-881. doi: 10.1002/jbmr.3053. Epub 2017 Mar 3.

Abstract

We have previously shown that endochondral ossification is finely regulated by the Clock system expressed in chondrocytes during postnatal skeletogenesis. Here we show a sophisticated modulation of bone resorption and bone mass by the Clock system through its expression in bone-forming osteoblasts. Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) and Period1 (Per1) were expressed with oscillatory rhythmicity in the bone in vivo, and circadian rhythm was also observed in cultured osteoblasts of Per1::luciferase transgenic mice. Global deletion of murine Bmal1, a core component of the Clock system, led to a low bone mass, associated with increased bone resorption. This phenotype was recapitulated by the deletion of Bmal1 in osteoblasts alone. Co-culture experiments revealed that Bmal1-deficient osteoblasts have a higher ability to support osteoclastogenesis. Moreover, 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ]-induced receptor activator of nuclear factor κB ligand (Rankl) expression was more strongly enhanced in both Bmal1-deficient bone and cultured osteoblasts, whereas overexpression of Bmal1/Clock conversely inhibited it in osteoblasts. These results suggest that bone resorption and bone mass are regulated at a sophisticated level by osteoblastic Clock system through a mechanism relevant to the modulation of 1,25(OH)2 D3 -induced Rankl expression in osteoblasts. © 2017 American Society for Bone and Mineral Research.

Keywords: BONE RESORPTION; CLOCK; OSTEOBLASTS; RANKL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism*
  • Animals
  • Bone Resorption / genetics
  • Bone Resorption / metabolism*
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism*
  • Cells, Cultured
  • Mice
  • Mice, Knockout
  • Osteoblasts / metabolism*
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism*
  • RANK Ligand / genetics
  • RANK Ligand / metabolism*

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Period Circadian Proteins
  • RANK Ligand
  • Tnfsf11 protein, mouse
  • CLOCK Proteins
  • Clock protein, mouse