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 β2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin1. 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 function2. 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 mouse3. 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 mice4, 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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Takeda, S. et al. Leptin regulates bone formation via the sympathetic nervous system. Cell 111, 305–317 (2002)
Yang, X. et al. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell 117, 387–398 (2004)
Ducy, P. et al. Leptin inhibits bone formation through a hypothalamic relay: A central control of bone mass. Cell 100, 197–207 (2000)
Kristensen, P. et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393, 72–76 (1998)
Chruscinski, A. J. et al. Targeted disruption of the beta2 adrenergic receptor gene. J. Biol. Chem. 274, 16694–16700 (1999)
Thomas, S. A., Matsumoto, A. M. & Palmiter, R. D. Noradrenaline is essential for mouse fetal development. Nature 374, 643–646 (1995)
Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998)
Dominici, M. et al. Hematopoietic cells and osteoblasts are derived from a common marrow progenitor after bone marrow transplantation. Proc. Natl Acad. Sci. USA 101, 11761–11766 (2004)
Teitelbaum, S. L. & Ross, F. P. Genetic regulation of osteoclast development and function. Nature Rev. Genet. 4, 638–649 (2003)
Lacey, D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998)
Berkowitz, L. A., Riabowol, K. T. & Gilman, M. Z. Multiple sequence elements of a single functional class are required for cyclic AMP responsiveness of the mouse c-fos promoter. Mol. Cell. Biol. 9, 4272–4281 (1989)
Asnicar, M. A. et al. Absence of cocaine- and amphetamine-regulated transcript results in obesity in mice fed a high caloric diet. Endocrinology 142, 4394–4400 (2001)
Satoh, N. et al. Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion. Diabetes 48, 1787–1793 (1999)
Orwoll, B., Bouxsein, M. L., Marks, D. L., Cone, R. D. & Klein, R. F. in ORS/AAOS Presentations 2003, 71st Annual Meeting of the AAOS (ORS, San Francisco, CA, 2004).
Rohrer, D. K., Chruscinski, A., Schauble, E. H., Bernstein, D. & Kobilka, B. K. Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors. J. Biol. Chem. 274, 16701–16708 (1999)
Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997)
Takahashi, N. et al. Osteoblastic cells are involved in osteoclast formation. Endocrinology 123, 2600–2602 (1988)
Ducy, P. & Karsenty, G. Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene. Mol. Cell. Biol. 15, 1858–1869 (1995)
We thank T. Townes and A. Hanauer for Atf4 and Rsk2 - / - mice, A. Hanauer and M. Montminy for RSK2 and CREB antibodies, M. Huelskamp and D.A. Horst for Dpd and CTX measurements, P. Ducy for suggestions and critical readings of the manuscript, and L. Li for technical assistance This work was supported by grants from NIH, NSBRI and CNRC (G.K., F.E.), Arthritis Foundation (S.T.) and Children's Brittle Bone Foundation (X.Y.).
The authors declare that they have no competing financial interests.
About this article
Cite this article
Elefteriou, F., Ahn, J., Takeda, S. et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434, 514–520 (2005). https://doi.org/10.1038/nature03398
Best Practice & Research Clinical Endocrinology & Metabolism (2021)
Journal of Clinical Investigation (2021)
Frontiers in Physiology (2021)
Endocrinología, Diabetes y Nutrición (2021)