Background/Purpose: Genetic disruption of the circadian molecular clock in mice is a powerful tool to dissect the role of circadian rhythms in health and disease. Several bone turnover markers show circadian variation in humans suggesting a function for the circadian molecular clock in bone physiology. In contrast to previous reports, we found that at 8 weeks of age (prior to the onset of heterotopic ossification) mice with germline deletion of the core circadian regulator Bmal1 (Brain and muscle Arntl-like 1, Bmal1^-/-) have reduced trabecular and cortical bone compared with wildtype mice. Here, we ask whether the development of this phenotype can be mapped to disruption of the molecular clock in mesenchymal cells, osteoclasts, or both.

Methods: We generated mice with conditional deletion of Bmal1 in mesenchymal cells of the limbs (Prx1-cre) or osteoclasts (Ctk-cre). We analyzed the bone phenotype of 8 week-old male mice comparing Bmal1^fl/fl.Prx1-cre mice with Bmal1^fl/fl littermate controls, and Bmal1^fl/fl.Ctk-cre mice with Bmal1^fl/+.Ctk-cre littermate controls, respectively. Femurs were examined by micro-computed tomography and histology, and in vitroosteoclast and osteoblast differentiation assays were performed. 

Results: Deletion of Bmal1 in osteoclasts had no effect on in vitro osteoclast differentiation or resorptive function. Consistent with this, no differences in trabecular or cortical bone parameters were seen in Bmal1^fl/fl.Ctk-cre compared with Bmal1^fl/+.Ctk-cre controls. In contrast, we found a significant reduction of trabecular bone in Bmal1^fl/fl.Prx1-cre mice compared with controls (BV/TV 14.9% vs. 20.5% p=0.002; n=14) with corresponding significant changes in trabecular number, thickness, spacing and connectivity. Cortical parameters were also affected (C.Th.  0.15mm vs 0.17mm, p=0.008; n=14). In vitro assays failed to reveal an effect of mesenchymal Bmal1 deletion on osteoclast formation or function. Differentiation of osteoblasts from Bmal1^fl/fl.Prx1-cre bone marrow stromal cells was also not significantly different from controls. 

Conclusion: These results demonstrate that bone mass in mice is controlled by the cell-intrinsic circadian molecular clock in mesenchymal cells, whereas a functioning clock in osteoclasts appears dispensable for maintaining bone homeostasis.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/defective-circadian-control-in-mesenchymal-cells-reduces-adult-bone-mass/