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Leptin regulation of bone resorption by the sympathetic nervous system and CART
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 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…
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“A polymorphism of the first intron of the gene coding for the type I collagen α1 chain and increased levels of homocysteine can influence fracture risk independent of BMD”
From Pathogenesis of osteoporosis: concepts, conflicts, and prospects (2005) · cites this paper as [101]
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BackgroundInfluentialDeficiency of GD3 Synthase in Mice Resulting in the Attenuation of Bone Loss with Aging
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Self-citationβ‐Blockade: Benefits Beyond Blood Pressure Reduction?
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Minireview: Complexity of Hematopoietic Stem Cell Regulation in the Bone Marrow Microenvironment
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Foxo1 regulates Dbh expression and the activity of the sympathetic nervous system in vivo
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“Leptin deficiency seems to decrease adrenergic tone(14) and to affect the release of noradrenaline from sympathetic nerve fibers.(15) Noradrenaline binds to A2-adrenergic receptors on osteoblasts and inhibits bone formation.”
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“Sympathetic signaling through ATF4 up-regulates RANK-L to increase resorption; this effect is inhibited by CART (cocaine amphetamine-related transcript), a leptin-regulated neuropeptide (82).”
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“Adiponectin stimulates the proliferation, differentiation and mineralization of osteoblastic cells [3, 4].”
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BackgroundNeuronal regulation of bone and tendon injury repair: a focused review
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“Defective osteoclast formation was shown in osteoblast‐bone marrow cell (BMC) cocultures prepared from Adrb2 mice which lack RANKL expression.(5) In our previous work,(11) β1‐ARs‐mediated and β2‐ARs‐mediated signaling play reciprocal roles in the regulation of osteoclastogenesis via osteocytic RANKL expression.”
BackgroundBrain-Derived Acetylcholine Maintains Peak Bone Mass in Adult Female Mice
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Self-citationNorepinephrine modulates IL-1β-induced catabolic response of human chondrocytes
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“2-AG is an activator of CB1R and results in inhibition of norepinephrine release, thus stimulating new bone formation [119, 120].”
BackgroundBone Tissue and the Nervous System: What Do They Have in Common?
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“Receptor Activator for NF-kappaB Ligand Osteoclast differentiation marker [ 78 ]”
Backgroundβ-1 Adrenergic Agonist Mitigates Unloading-Induced Bone Loss by Maintaining Formation
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PTH Regulates β2‐Adrenergic Receptor Expression in Osteoblast‐Like MC3T3‐E1 Cells
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“Beta2 adrenergic receptor mediates sympathetic tone [Takeda et al., 2002; Elefteriou et al., 2005; Elefteriou, 2008] and has been implicated in bone loss in the animal models used to investigate pathophysiology of disuse osteoporosis [Kondo et al., 2005; Hino et al., 2006] using hind limb unloading…”
BackgroundSelf-citationShi, Y., Shu, Z.-J., Xue, X., Yeh, C., Katz, M. S., & Kamat, A. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.03.005 · Cited by 20
“A number of studies have been conducted using young (2–6 mo old) β2-AR KO animals (Ma et al., 2011; Elefteriou et al., 2005; Chruscinski et al., 1999; Santulli et al., 2012; Wang et al., 2013; Jiang et al., 2013; Fernandes et al., 2014); however, to our knowledge, the current studies are the first…”
Adiponectin Interactions in Bone and Cartilage Biology and Disease
Ruscica, M., Steffani, L., & Magni, P. (2012) · Vitamins and hormones · doi:10.1016/b978-0-12-398313-8.00012-9 · Cited by 19
Hipp, J. A., & Hayes, W. C. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-2220-6.10003-9 · Cited by 19
Zhang, X., Tian, L., Majumdar, A., & Scheller, E. L. (2024) · Comprehensive Physiology · doi:10.1002/j.2040-4603.2024.tb00300.x · Cited by 18
Neuroregulation during Bone Formation and Regeneration: Mechanisms and Strategies
Zhao, X., Yao, M., Wang, Y., Feng, C., Yang, Y., Tian, L., Bao, C., Li, X., Zhu, X., & Zhang, X. (2025) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.4c16786 · Cited by 20
Liu, M., Liu, Y., Yu, J., Gong, J., Zhao, C., & Liu, Z. (2025) · Bone Research · doi:10.1038/s41413-025-00494-1 · Cited by 19
Age-Related Changes in Muscle and Bone
Pasco, J. A. (2019) · Springer eBooks · doi:10.1007/978-3-030-25890-0_3 · Cited by 19
The role of the RANKL/RANK/OPG system in the central nervous systems (CNS)
Hanada, R. (2020) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-020-01143-9 · Cited by 18
Peripheral nerves in the tibial subchondral bone
Sun, Q., Li, G., Liu, D., Xie, W., Xiao, W., Li, Y., & Cai, M. (2022) · Bone and Joint Research · doi:10.1302/2046-3758.117.bjr-2021-0355.r1 · Cited by 19
Bone mass loss in chronic heart failure is associated with sympathetic nerve activation
Guan, Z., Yuan, W., Jia, J., Zhang, C., Zhu, J., Huang, J., Zhang, W., Fan, D., Leng, H., Li, Z., et al. (2022) · Bone · doi:10.1016/j.bone.2022.116596 · Cited by 18
The Role of Sympathetic Nerves in Osteoporosis: A Narrative Review
Zhang, W., Liu, Y., Xu, J., Chen, F., Zhang, B., Feng, P., Wang, Y., & Kong, Q. (2022) · Biomedicines · doi:10.3390/biomedicines11010033 · Cited by 18
The interplay between bone and heart health as reflected in medication effects: A narrative review
Trost, S. U., Tesfaye, N., & Harindhanavudhi, T. (2023) · Women s Health · doi:10.1177/17455057231165549 · Cited by 19
Xu, H., Liu, J.-X., Zheng, C., Liu, L., Ma, C., Tian, J.-Y., Yuan, Y., Cao, Y., Xing, S., Liu, S., et al. (2023) · iScience · doi:10.1016/j.isci.2023.107455 · Cited by 18
Engineering Innervated Musculoskeletal Tissues for Regenerative Orthopedics and Disease Modeling
Zhou, Z., Liu, J., Xiong, T., Liu, Y., Tuan, R. S., & Li, Z. A. (2024) · Small · doi:10.1002/smll.202310614 · Cited by 19
Anorexia, bulimia, and the athletic triad: Evaluation and management
Fenichel, R. M., & Warren, M. P. (2007) · Current Osteoporosis Reports · doi:10.1007/s11914-007-0011-3 · Cited by 18
Bonnet, É., Ruidavets, J., Genoux, A., Mabile, L., Busato, F., Obadia, M., Prévoteau, F., Marchou, B., Massip, P., Marion-Latard, F., et al. (2013) · BMC Infectious Diseases · doi:10.1186/1471-2334-13-293 · Cited by 18
“Activation of the β2-adrenergic receptor in osteoblasts stimulates RANKL expression [30].”
Mouse models of neurological disorders: A view from the blood–brain barrier
Banks, W. A. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.10.011 · Cited by 22
Cocchi, M., Tonello, L., Gabrielli, F., & Pregnolato, M. (2011) · Annals of General Psychiatry · doi:10.1186/1744-859x-10-9 · Cited by 18
“Firstly, with respect to the mechanism of bone loss from sympathetic activity, activated adrenergic receptors on osteoblasts suppress critical transcription factors necessary for bone formation but also enhance osteoclastogenesis, principally by upregulating the osteoclast differentiation factor receptor activator of…”
BackgroundActivation of Protein Kinase A in Mature Osteoblasts Promotes a Major Bone Anabolic Response
Tascau, L., Gardner, T. R., Anan, H., Yongpravat, C., Cardozo, C. P., Bauman, W. A., Lee, F. Y., Oh, D. S., & Tawfeek, H. A. W. (2015) · Endocrinology · doi:10.1210/en.2015-1614 · Cited by 19
Impact of renin-angiotensin system inhibitors and beta-blockers on dental implant stability
Saravi, B., Vollmer, A., Lang, G. M., Adolphs, N., Li, Z., Giers, V., & Stoll, P. (2021) · International Journal of Implant Dentistry · doi:10.1186/s40729-021-00309-y · Cited by 18
Gonciulea, A. R., & de Beur, S. M. J. (2015) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-015-9316-1 · Cited by 18
“This hypothalamic decrease in serotonin signaling results in increased activation of the sympathetic nervous system and negative regulation of bone mass through the β2-adrenergic receptors expressed in osteoblasts [111].”
BackgroundRegulation of hematopoietic niches by sympathetic innervation
Aguila, H. L. (2006) · BioEssays · doi:10.1002/bies.20427 · Cited by 18
The role of catecholamines in mesenchymal stem cell fate
Hajifathali, A., Saba, F., Atashi, A., Soleimani, M., Mortaz, E., & Rasekhi, M. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-1984-8 · Cited by 18
“density without affecting body weight (Elefteriou et al. 2005).”
Effects of Sympathetic Innervation Loss on Mandibular Distraction Osteogenesis
Wang, T., Cao, J., Du, Z.-J., Zhang, Y.-B., Liu, Y., Wang, L., & Lei, D. (2012) · Journal of Craniofacial Surgery · doi:10.1097/scs.0b013e31825daab2 · Cited by 18
“Therefore, sympathetic innervation loss may result in inhibition of bone resorption.(20,36) It is still unknown why the bone phenotype recovered to some extent after long term of consolidation.”
BackgroundObesity susceptibility CART gene polymorphism contributes to bone remodeling in postmenopausal women
Guérardel, A., Tankó, L. B., Boutin, P., Christiansen, C., & Froguel, P. (2005) · Osteoporosis International · doi:10.1007/s00198-005-2022-1 · Cited by 18
“Conversely, it was suggested that hypothalamic neurones expressing CART (cocaineand amphetamine-regulated transcript) may counter leptin-induced bone resorption [1].”
BackgroundRole of RANKL Signaling in Bone Homeostasis
Sobacchi, C., Menale, C., Crisafulli, L., & Ficara, F. (2024) · Physiology · doi:10.1152/physiol.00031.2024 · Cited by 18
Zhang, K., Hu, H., Sun, Y., Nan, J., Liu, W., Lei, P., & Hu, Y. (2023) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2023.113506 · Cited by 18
The haematopoietic stem cell niche: a new player in cardiovascular disease?
Al‐Sharea, A., Lee, M. K. S., Purton, L. E., Hawkins, E. D., & Murphy, A. J. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy308 · Cited by 18
Crosstalk between the brain and bone.
Masi, L. (2012) · Europe PMC (PubMed Central) · Cited by 17
The Skeleton and the Sympathetic Nervous System: It's about Time!
Motyl, K. J., & Rosen, C. J. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3205 · Cited by 17
Influence of Hormonal Appetite and Energy Regulators on Bone
Khor, E. C., Wee, N. K. Y., & Baldock, P. A. J. (2013) · Current Osteoporosis Reports · doi:10.1007/s11914-013-0157-0 · Cited by 17
“However, the biological significance of the elevation in cancellous bone in ob/ob, mediated by adrenergic signalling [15, 63, 64], and also evident in caloric restriction [80], remains elusive.”
The hypothalamic control of bone mass, implication for the treatment of osteoporosis
Karsenty, G., & Ducy, P. F. (2006) · Annales d Endocrinologie · doi:10.1016/s0003-4266(06)72566-5 · Cited by 17
Self-citationBone signaling pathways and treatment of osteoporosis
Gogakos, A. I., Cheung, M., Bassett, J. H. D., & Williams, G. R. (2009) · Expert Review of Endocrinology & Metabolism · doi:10.1586/eem.09.38 · Cited by 17
Bone Health in Adrenal Disorders
Kim, B., Lee, S. H., & Koh, J. (2018) · Endocrinology and Metabolism · doi:10.3803/enm.2018.33.1.1 · Cited by 17
Metadata
- Authors
- Elefteriou, F., Ahn, J. D., Takeda, S., Starbuck, M., Yang, X., Liu, X., Kondo, H., Richards, W. G., Bannon, T. W., Noda, M., Clement, K., Vaisse, C., & Karsenty, G.
- Affiliations
- Baylor College of Medicine (US)
- Tokyo Medical and Dental University (JP)
- Amgen (United States) (US)
- University of California, San Francisco (US)
- ORCID
- Venue
- Nature
- Published
- 2005-02-20
- Volume
- 434
- Issue
- 7032
- Pages
- 514-520
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1997508587
- Cited by
- 1,311
- References
- 17
- Citations by year
- 2026: 45 · 2025: 46 · 2024: 55 · 2023: 43 · 2022: 38 · 2021: 59 · 2020: 51 · 2019: 48 · 2018: 51 · 2017: 52 · 2016: 53 · 2015: 69 · 2014: 83 · 2013: 67 · 2012: 84
- FWCI
- 30.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK060540)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- leptin, bone resorption, bone remodeling, sympathetic nervous system, osteoclastogenesis, RANKL, beta2-adrenergic receptor, protein kinase A, osteoblasts, gonadectomy, osteoporosis, ob/ob mice, gonadal failure
- MeSH terms
- Cocaine- and Amphetamine-Regulated Transcript Protein, Amino Acid Sequence, Animals, Bone Resorption, Carrier Proteins, Cell Line, Child, Child, Preschool, Humans, Male, Membrane Glycoproteins, Models, Neurological, Neoplasm Proteins, Nerve Tissue Proteins, Osteoblasts, Osteogenesis, Sympathetic Nervous System, Transcription Factors, Signal Transduction, Gene Deletion, Cyclic AMP-Dependent Protein Kinases, Receptors, Adrenergic, beta-2, Response Elements, Leptin, Receptor, Melanocortin, Type 4, Mice, Activating Transcription Factor 4, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Receptors, Leptin
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