The Molecular Clock Mediates Leptin-Regulated Bone Formation

• Published in: Cell Vol. 122; no. 5; pp. 803 - 815
• Main Authors: Fu, Loning, Patel, Millan S., Bradley, Allan, Wagner, Erwin F., Karsenty, Gerard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.09.2005
• Subjects: Animals; Bone Density - drug effects; Bone Density - physiology; Bone Remodeling - drug effects; Bone Remodeling - physiology; Cell Cycle Proteins; Cell Proliferation - drug effects; Circadian Rhythm - genetics; Circadian Rhythm - physiology; Gene Expression Regulation, Developmental - drug effects; Humans; Leptin - metabolism; Leptin - pharmacology; Mice; Mice, Knockout; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - physiology; Period Circadian Proteins; Phenotype; Signal Transduction - drug effects; Signal Transduction - physiology; Stromal Cells - drug effects; Stromal Cells - physiology; Sympathetic Nervous System - metabolism; Transcription Factor AP-1 - drug effects; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - physiology; Non-programmatic
• ISSN: 0092-8674
• DOI: 10.1016/j.cell.2005.06.028

The hormone leptin is a regulator of bone remodeling, a homeostatic function maintaining bone mass constant. Mice lacking molecular-clock components ( Per and Cry), or lacking Per genes in osteoblasts, display high bone mass, suggesting that bone remodeling may also be subject to circadian regulation. Moreover, Per-deficient mice experience a paradoxical increase in bone mass following leptin intracerebroventricular infusion. Thus, clock genes may mediate the leptin-dependent sympathetic regulation of bone formation. We show that expression of clock genes in osteoblasts is regulated by the sympathetic nervous system and leptin. Clock genes mediate the antiproliferative function of sympathetic signaling by inhibiting G1 cyclin expression. Partially antagonizing this inhibitory loop, leptin also upregulates AP-1 gene expression, which promotes cyclin D1 expression, osteoblast proliferation, and bone formation. Thus, leptin determines the extent of bone formation by modulating, via sympathetic signaling, osteoblast proliferation through two antagonistic pathways, one of which involves the molecular clock.