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

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, Bmal1 f/f .Prx1-cre mice had significantly less trabecular and cortical bone than Bmal1 f/f littermate controls, recapitulating the bone phenotype of Bmal1 germline deficient mice. The number of osteoblast precursors in the bone marrow of Bmal1 f/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 Bmal1 f/f .Prx1-cre mice than in Bmal1 f/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 Bmal1 f/f .Prx1-cre mice had a higher number of tartrate resistant acid phosphatase (TRAP) positive osteoclasts than Bmal1 f/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. Highlights • Bmal1 −/− mice with genetic disruption of the circadian molecular clock have a low bone mass phenotype. • The bone phenotype of Bmal1 −/− mice is recapitulated in mice with conditional Bmal1 deletion in mesenchymal cells (Bmal1 f/f .Prx1-cre). • Bmal1 f/f .Prx1-cre mice exhibit high bone turnover with enhanced bone resorption and bone formation. [ABSTRACT FROM AUTHOR]