Leptin regulation of bone resorption by the sympathetic nervous system and CART (original) (raw)

Nature volume 434, pages 514–520 (2005)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Takeda, S. et al. Leptin regulates bone formation via the sympathetic nervous system. Cell 111, 305–317 (2002)
    Article CAS Google Scholar
  2. 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)
    Article CAS Google Scholar
  3. Ducy, P. et al. Leptin inhibits bone formation through a hypothalamic relay: A central control of bone mass. Cell 100, 197–207 (2000)
    Article CAS Google Scholar
  4. Kristensen, P. et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393, 72–76 (1998)
    Article ADS CAS Google Scholar
  5. Chruscinski, A. J. et al. Targeted disruption of the beta2 adrenergic receptor gene. J. Biol. Chem. 274, 16694–16700 (1999)
    Article CAS Google Scholar
  6. Thomas, S. A., Matsumoto, A. M. & Palmiter, R. D. Noradrenaline is essential for mouse fetal development. Nature 374, 643–646 (1995)
    Article ADS CAS Google Scholar
  7. Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998)
    Article ADS CAS Google Scholar
  8. 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)
    Article ADS CAS Google Scholar
  9. Teitelbaum, S. L. & Ross, F. P. Genetic regulation of osteoclast development and function. Nature Rev. Genet. 4, 638–649 (2003)
    Article CAS Google Scholar
  10. Lacey, D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998)
    Article CAS Google Scholar
  11. 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)
    Article CAS Google Scholar
  12. 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)
    Article CAS Google Scholar
  13. Satoh, N. et al. Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion. Diabetes 48, 1787–1793 (1999)
    Article CAS Google Scholar
  14. 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).
  15. 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)
    Article CAS Google Scholar
  16. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997)
    Article CAS Google Scholar
  17. Takahashi, N. et al. Osteoblastic cells are involved in osteoclast formation. Endocrinology 123, 2600–2602 (1988)
    Article CAS Google Scholar
  18. 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)
    Article CAS Google Scholar

Download references

Acknowledgements

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.).

Author information

Authors and Affiliations

  1. Department of Molecular and Human Genetics,
    Florent Elefteriou, Jong Deok Ahn, Shu Takeda, Michael Starbuck, Xiangli Yang, Xiuyun Liu & Gerard Karsenty
  2. Bone Disease Program of Texas,
    Florent Elefteriou, Jong Deok Ahn, Shu Takeda, Michael Starbuck, Xiangli Yang, Xiuyun Liu & Gerard Karsenty
  3. Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, 77030, USA
    Florent Elefteriou & Gerard Karsenty
  4. Department of Orthopedics,
    Shu Takeda
  5. Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone,
    Shu Takeda, Hisataka Kondo & Masaki Noda
  6. Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 101-0062, Tokyo, Japan
    Hisataka Kondo & Masaki Noda
  7. Amgen Inc., Neuroscience, Thousand Oaks, California, 91320, USA
    William G. Richards & Tony W. Bannon
  8. INSERM Avenir team–University Paris 6, EA3502
    Karine Clement
  9. CHRU Pitié Salpétrière, Hôtel-Dieu Nutrition Department, F-75004, Paris, France
    Karine Clement
  10. Diabetes Center and Department of Medicine, University of California San Francisco, San Francisco, California, 94143, USA
    Christian Vaisse

Authors

  1. Florent Elefteriou
    You can also search for this author inPubMed Google Scholar
  2. Jong Deok Ahn
    You can also search for this author inPubMed Google Scholar
  3. Shu Takeda
    You can also search for this author inPubMed Google Scholar
  4. Michael Starbuck
    You can also search for this author inPubMed Google Scholar
  5. Xiangli Yang
    You can also search for this author inPubMed Google Scholar
  6. Xiuyun Liu
    You can also search for this author inPubMed Google Scholar
  7. Hisataka Kondo
    You can also search for this author inPubMed Google Scholar
  8. William G. Richards
    You can also search for this author inPubMed Google Scholar
  9. Tony W. Bannon
    You can also search for this author inPubMed Google Scholar
  10. Masaki Noda
    You can also search for this author inPubMed Google Scholar
  11. Karine Clement
    You can also search for this author inPubMed Google Scholar
  12. Christian Vaisse
    You can also search for this author inPubMed Google Scholar
  13. Gerard Karsenty
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toGerard Karsenty.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

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

Download citation

This article is cited by

Editorial Summary

Bone structure and function are maintained by bone remodelling, a balance of bone resorption by osteoclasts and bone formation by osteoblasts. New work in mice suggests that leptin, best known as a hormone regulating body weight, may play a major role in striking this balance. In one pathway, leptin stimulation of sympathetic neurons promotes differentiation of osteoclasts (and resorption) and in the other, a neuropeptide called CART inhibits osteoclast differentiation. Blockade of the leptin-regulated neural pathway might help prevent bone loss in osteoporosis.

Associated content