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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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BackgroundInner Ear Vestibular Signals Regulate Bone Remodeling via the Sympathetic Nervous System
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BackgroundSelf-citationBone Resorption Is Increased in Pheochromocytoma Patients and Normalizes following Adrenalectomy
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Cocaine and Amphetamine-Regulated Transcript May Regulate Bone Remodeling as a Circulating Molecule
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“The possibility exist that it acts locally on bone cells, although in vitro or in coculture experiments, we failed to see an effect of CART on bone cells (7).”
BackgroundMethodResultInfluentialSelf-citationBone remodeling is regulated by inner ear vestibular signals
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BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway
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“Genetic experiments have established that leptin is a powerful inhibitor of bone mass accrual: in the absence of leptin, mice and humans have increased bone mass [1,6].”
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“The loss of one or two copies of CART showed significantly reduced bone mass in MC4R mutant mice (Elefteriou et al., 2005).”
BackgroundResultInfluentialDo polyunsaturated fatty acids protect against bone loss in our aging and osteoporotic population?
Martyniak, K., Wei, F., Ballesteros, A., Meckmongkol, T. T., Calder, A. N., Gilbertson, T. A., Orlovskaya, N. A., & Coathup, M. J. (2020) · Bone · doi:10.1016/j.bone.2020.115736 · Cited by 52
Different sympathetic pathways control the metabolism of distinct bone envelopes
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“The catecholaminergic system regulates trabecular bone formation and resorption in long bones [12,13,37,38] while the cholinergic pathway may control bone resorption in the mandible periosteum.”
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Lecka‐Czernik, B., & Stechschulte, L. A. (2014) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.06.010 · Cited by 48
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Propranolol enhances bone healing and implant osseointegration in rats tibiae
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Resolving the Two “Bony” Faces of PPAR- γ
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Osteoporosis and Alveolar Bone Health in Periodontitis Niche: A Predisposing Factors-Centered Review
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“Adipokine leptin participates in the regulation of bone metabolism directly via activating leptin receptors on osteoblasts and indirectly via activating sympathetic signaling [194].”
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Should I Lay or Should I Grow: Photoperiodic Versus Metabolic Cues in Chickens
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“Similarly, other studies have reported an effect of the sympathetic nervous system on regulation of bone mass.(46) Others have speculated that the mechanism of low BMD or BMC and depression in adult humans could be due to hypothalamic-pituitary-adrenal axis dysregulation, another arm of the stress system.”
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“Mutant mice lacking β2-AR have increased bone mass but do not respond to leptin by reduction in bone mass [53], while ovariectomized β2-AR null mice fail to lose bone mass, suggesting that maintenance of the sympathetic nervous system in bone may require estrogen, which is essential in regulating bone remodeling via t…”
BackgroundMinireview: Neural Signaling of Estradiol in the Hypothalamus
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Integrative Physiology: Defined Novel Metabolic Roles of Osteocalcin
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“The second, more recently defined, osteogenic influence of leptin involves modulation of cocaine and amphetamine-regulated transcript (CART) (12), a hypothalamic neuropeptide encoded by the CARTPT gene whose expression is increased by leptin (17).”
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Neuronal hypothalamic regulation of body metabolism and bone density is galanin dependent
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Bone circuitry and interorgan skeletal crosstalk
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“Leptinmediated SNS activation promotes osteoclastogenesis through increased RANKL expression, which is counteracted by increased secretion of the neuropeptide CART by the hypothalamus secondary to leptin- LEPR binding (Elefteriou et al., 2005).”
BackgroundThe roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies
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“In particular, β-adrenergic signals negatively regulate bone mass through the action of osteoblasts to produce RANKL and promote osteoclastogenesis.(98) In contrast, signaling from the parasympathetic nervous system positively regulates bone mass by activating nicotinic receptors on osteoclasts, which subsequently ind…”
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“At the same time the PKA activation of ATF4, another member of the CREB family of transcription factors, upregulates RANKL transcription and secretion, that consequently induces osteoclast activity [Elefteriou et al., 2005].”
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“healing (Elefteriou et al., 2005; Ma et al., 2013; Wang et al., 2010), and mobilize bone marrow hematopoietic stem cells from their niche (Katayama et al.”
BackgroundCharacterization of the Two CART Genes (CART1 and CART2) in Chickens (Gallus gallus)
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“A PKA phosphorylation site (serine 254) within the ATF4 molecule was recently shown to mediate -adrenergic induction of Rankl mRNA expression in osteoblasts (54).”
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“CART is a hypothalamic signaling that inhibits bone resorption via RANKL modulation (Elefteriou et al., 2005).”
Mechanistic complexities of bone loss in Alzheimer’s disease: a review
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Studies of cocaine- and amphetamine-regulated transcript (CART) knockout mice
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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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