Leptin regulation of bone resorption by the sympathetic nervous system and CART.
Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.
Elefteriou
Florent
F
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Ahn
Jong Deok
JD
Takeda
Shu
S
Starbuck
Michael
M
Yang
Xiangli
X
Liu
Xiuyun
X
Kondo
Hisataka
H
Richards
William G
WG
Bannon
Tony W
TW
Noda
Masaki
M
Clement
Karine
K
Vaisse
Christian
C
Karsenty
Gerard
G
D051701:Activating Transcription Factor 4; D000595:Amino Acid Sequence; D000818:Animals; D001862:Bone Resorption; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D020738:Leptin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008959:Models, Neurological; D009363:Neoplasm Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency / Q000235:genetics; D054411:Receptors, Leptin; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
C497109:ATF4 protein, human; D002352:Carrier Proteins; C515448:LEPR protein, human; D020738:Leptin; C470072:MC4R protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D044105:Receptor, Melanocortin, Type 4; D018343:Receptors, Adrenergic, beta-2; D054411:Receptors, Leptin; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; C515447:leptin receptor, mouse; D051701:Activating Transcription Factor 4; D017868:Cyclic AMP-Dependent Protein Kinases