The circadian modulation of leptin-controlled bone formation.

Mice with circadian gene Period and Cryptochrome mutations develop high bone mass early in life. Such a phenotype is accompanied by an increase in osteoblast numbers in mutant bone and cannot be corrected by leptin intracerebroventricular infusion. Thus, the molecular clock plays a key role in leptin-mediated sympathetic regulation of bone formation. Indeed, we found that leptin-dependent sympathetic signaling induces the expression of AP1 and circadian genes in bone and in osteoblasts with similar kinetics, and these two pathways play opposite roles in controlling c-myc expression. Mutations in the Period 1 and 2 genes result in uncontrolled c-myc signaling, overexpression of G1 cyclins, and increased osteoblast proliferation and bone-formation parameters. These results indicate that the role of leptin-dependent sympathetic signaling in bone formation is achieved through regulating two antagonistic pathways in osteoblasts.