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.
Fu
Loning
L
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Patel
Millan S
MS
Karsenty
Gerard
G
D000818:Animals; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020738:Leptin / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009687:Nuclear Proteins; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D056950:Period Circadian Proteins; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors
D018797:Cell Cycle Proteins; D020738:Leptin; D009687:Nuclear Proteins; C539022:PER1 protein, human; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors