The Clock Genes Period 2 and Cryptochrome 2 Differentially Balance Bone Formation

BACKGROUND: Clock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype. METHODOLOGY/PRINCIPAL FINDINGS: We found that Per2(Brdm1) mutant mice as well as mice lacking Cry2(−/−) displayed significantly increased bone volume at 12 weeks of age, when bone turnover is high. Per2(Brdm1) mutant mice showed alterations in parameters specific for osteoblasts whereas mice lacking Cry2(−/−) displayed changes in osteoclast specific parameters. Interestingly, inactivation of both Per2 and Cry2 genes leads to normal bone volume as observed in wild type animals. Importantly, osteoclast parameters affected due to the lack of Cry2, remained at the level seen in the Cry2(−/−) mutants despite the simultaneous inactivation of Per2. CONCLUSIONS/SIGNIFICANCE: This indicates that Cry2 and Per2 affect distinct pathways in the regulation of bone volume with Cry2 influencing mostly the osteoclastic cellular component of bone and Per2 acting on osteoblast parameters.