Defective circadian control in mesenchymal cells reduces adult bone mass in mice by promoting osteoclast function

Bone. 2019 Apr;121:172-180. doi: 10.1016/j.bone.2019.01.016. Epub 2019 Jan 16.

Abstract

Serum bone turnover markers show diurnal variation in humans, suggesting that circadian rhythms contribute to normal bone physiology. This conclusion is corroborated by bone phenotypes in mice with genetic disruption of the circadian molecular clock mechanism, for instance via deletion of the transcription factor Brain and Muscle Arntl-like 1 (Bmal1). To dissect the contribution of circadian molecular clocks in individual bone cell types, we generated mice with conditional deletion of Bmal1 in osteoclasts (Ctsk-cre) and in mesenchymal cells of the limbs (Prx1-cre). We report that deletion of Bmal1 in osteoclasts had no effect on trabecular or cortical bone parameters in vivo or on osteoclast differentiation in vitro. In contrast, Bmal1f/f.Prx1-cre mice had significantly less trabecular and cortical bone than Bmal1f/f littermate controls, recapitulating the bone phenotype of Bmal1 germline deficient mice. The number of osteoblast precursors in the bone marrow of Bmal1f/f.Prx1-cre mice was similar to wild-type controls, while the in vitro differentiation capacity of Bmal1-deficient osteoblast precursors, measured as induction of alkaline phosphatase activity, was significantly lower. Despite this, serum procollagen type 1 N-terminal propeptide (P1NP), a measure of bone formation in vivo, was higher in Bmal1f/f.Prx1-cre mice than in Bmal1f/f mice. Consistent with a high bone turnover state in the mutant mice, the bone resorption marker serum C-terminal telopeptides of Type I collagen (CTX-I) was also elevated, and Bmal1f/f.Prx1-cre mice had a higher number of tartrate resistant acid phosphatase (TRAP) positive osteoclasts than Bmal1f/f controls. These results demonstrate that adult bone mass in mice is controlled by the intrinsic circadian molecular clock in mesenchymal cells but not osteoclasts. The effect of the mesenchymal cell clock on bone turnover appears to involve osteoblast-osteoclast cross-talk.

Keywords: Bone; Genetic animal models; MicroCT; Osteoblasts; Osteoclasts; Transcription factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density / physiology*
  • Cell Differentiation / physiology
  • Circadian Rhythm / physiology*
  • Female
  • Male
  • Mesenchymal Stem Cells / physiology*
  • Mice
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / metabolism
  • Osteogenesis / physiology*
  • Transcription Factors / metabolism
  • X-Ray Microtomography

Substances

  • Transcription Factors