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

Jan 20, 2019Bone

Faulty internal clock in bone-supporting cells lowers adult bone mass in mice by increasing bone breakdown

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Deletion of the circadian clock gene Bmal1 in mesenchymal cells results in significantly less trabecular and cortical bone in mice.

Serum bone turnover markers exhibit daily fluctuations, indicating a link between circadian rhythms and bone physiology.
Osteoclast-specific deletion of Bmal1 did not affect bone parameters or osteoclast differentiation.
Mice with Bmal1 deletion in mesenchymal cells showed reduced trabecular and cortical bone compared to controls.
Osteoblast precursors in the bone marrow of Bmal1-deficient mice had similar numbers to wild-type controls but lower differentiation capacity.
Higher levels of serum markers for bone formation and resorption were observed in Bmal1-deficient mesenchymal mice, suggesting increased bone turnover.

AI simplified

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.Prx1-cre mice had significantly less trabecular and cortical bone than Bmal1littermate controls, recapitulating the bone phenotype of Bmal1 germline deficient mice. The number of osteoblast precursors in the bone marrow of Bmal1.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.Prx1-cre mice than in Bmal1mice. 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.Prx1-cre mice had a higher number of tartrate resistant acid phosphatase (TRAP) positive osteoclasts than Bmal1controls. 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. f/f f/f f/f f/f f/f f/f f/f

Full Text

Full text is available at the source.

View full text (XML) ↗View full text ↗

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

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief