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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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The neuropeptide VIP regulates the expression of osteoclastogenic factors in osteoblasts
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“Previously, it has also been shown that isoproterenol stimulates RANKL expression in mouse calvarial osteoblasts and that this effect can be inhibited by the PKA inhibitor H89 [Elefteriou et al., 2005].”
BackgroundDNA synthesis of rat bone marrow mesenchymal stem cells through α1-adrenergic receptors
Han, J., Zou, Z., Zhu, C., Deng, J., Wang, J., Ran, X., Shi, C., Ai, G., Li, R., Cheng, T., et al. (2009) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2009.08.009 · Cited by 26
Neural surveillance of skeletal homeostasis
Zaidi, M. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.03.006 · Cited by 26
Saucedo, R., Rico, G., Vega, G., Basurto, L., Córdova, L. F. R., Galvan, R., Hernandez, M., Puello, E., & Zárate, A. (2014) · Journal of Endocrinological Investigation · doi:10.1007/s40618-014-0220-4 · Cited by 25
“Although this latter regulation should favor osteocalcin activation, the fact that Adrβ2 signaling also strongly favors Esp expression, and thus enhances osteoprotegerin secretion via the InsR/FOXO1 pathway offsets this effect [47, 48].”
BackgroundA Comprehensive Curated Reaction Map of Leptin Signaling Pathway
Nanjappa, V. (2011) · Journal of Proteomics & Bioinformatics · doi:10.4172/jpb.1000188 · Cited by 26
“Leptin also stimulates bone growth and acts as a suppressor of bone resorption [34,35].”
BackgroundInnervation of the tibial epiphysis through the intercondylar foramen
Matsuo, K., Ji, S., Miya, A., Yoda, M., Hamada, Y., Tanaka, T., Takao-Kawabata, R., Kawaai, K., Kuroda, Y., & Shibata, S. (2018) · Bone · doi:10.1016/j.bone.2018.11.007 · Cited by 26
Roles of osteoclasts in the control of medullary hematopoietic niches
Blin‐Wakkach, C., Rouleau, M., & Wakkach, A. (2014) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.06.032 · Cited by 26
Different skeletal regional response to continuous brain infusion of leptin in the rat
GUIDOBONO, F., Pagani, F., Sibilia, V., Netti, C., Lattuada, N., Rapetti, D., Mrak, E., Villa, I., Cavani, F., Bertoni, L., et al. (2005) · Peptides · doi:10.1016/j.peptides.2005.10.014 · Cited by 26
“Since an intact SNS is required for the action of central leptin on bone remodeling [6], it follows that under central leptin excess the activation of the SNS induces bone loss in the methaphyseal trabeculae without major impairment of mechanical competence, being cortical compartment unaffected.”
BackgroundInfluentialNeural regulation of bone marrow adipose tissue
Zhang, X., Hassan, M. G., & Scheller, E. L. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101522 · Cited by 24
Antipsychotic-induced bone loss: the role of dopamine, serotonin and adrenergic receptor signalling
Weerasinghe, D. K., Hodge, J. M., Pasco, J. A., Samarasinghe, R. M., Manavi, B. A., & Williams, L. J. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1184550 · Cited by 28
“Moreover, in animal studies, Adrb2-deficient mice have shown higher osteoblast activity and high bone mass with decreased resorption (Takeda et al., 2002; Elefteriou et al., 2005; Zhong and Xia, 2021).”
BackgroundRösch, G., Zaucke, F., & Jenei‐Lanzl, Z. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00039.2023 · Cited by 26
Pons, J., Evrard‐Todeschi, N., Bertho, G., Gharbi‐Benarous, J., Tanchou, V., Bénarous, R., & Girault, J. (2007) · Biochemistry · doi:10.1021/bi7014212 · Cited by 25
“In addition, ATF4 is important for cell proliferation and differentiation (8, 9). ATF4 is a critical regulator of osteoblast differentiation and function (10) and of bone resorption ( 11 ).”
BackgroundThe brain in bone and fuel metabolism
Wee, N. K. Y., Kulkarni, R. N., Horsnell, H. L., & Baldock, P. A. J. (2015) · Bone · doi:10.1016/j.bone.2015.10.020 · Cited by 26
“Moreover, MC4R mutant mice lacking one or two copies of CART exhibited a significantly lower bone mass [44,86], demonstrating that increased CART signalling plays an important role in the low-boneresorption/high-bone mass phenotype observed in MC4R null mice.”
BackgroundInfluentialTemperature dependence of the control of energy homeostasis requires CART signaling
Lau, J., Shi, Y., & Herzog, H. (2016) · Neuropeptides · doi:10.1016/j.npep.2016.03.006 · Cited by 25
“It is also worthy to note that our CART knockout mice as well as previously described models (Elefteriou et al., 2005; Gerrits et al., 2011) show a prominent low bone mass phenotype marked by reduced bone mineral density and content when held under RT conditions.”
BackgroundPawlak, D., Domaniewski, T., Znorko, B., Oksztulska-Kolanek, E., Lipowicz, P., Doroszko, M., Karbowska, M., & Pawlak, K. (2017) · Bone · doi:10.1016/j.bone.2017.08.004 · Cited by 25
The circadian modulation of leptin-controlled bone formation
Fu, L., Patel, M. S., & Karsenty, G. (2006) · Progress in brain research · doi:10.1016/s0079-6123(06)53010-9 · Cited by 25
Self-citationYamashiro, K., Myokai, F., Hiratsuka, K., Yamamoto, T., Senoo, K., Arai, H., Nishimura, F., Abiko, Y., & Takashiba, S. (2007) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2007.01.015 · Cited by 25
Transcriptional control of osteoblast differentiation and function
Karsenty, G. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814841-9.00007-5 · Cited by 25
Self-citationNovel perspectives on leptin in osteoarthritis: Focus on aging
Liu, Z., Xie, W., Li, H., Liu, X., Lu, Y., Lu, B., Deng, Z., & Li, Y. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.101159 · Cited by 30
“Norepinephrine is secreted from the terminal onto the b 2 adrenergic receptors of the osteoblasts, decreases bone formation, and increases receptor activator of nuclear factor kappa-B ligand expression and osteoclast differentiation, leading to increasing bone absorption 53 (Fig.”
BackgroundSelf-citationNeuromodulation of bone: Role of different peptides and their interactions (Review)
Wang, X., Xu, J., & Kang, Q. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11670 · Cited by 25
“Although SP can directly activate receptor activator of NF‑κB ligand (RANKL)‑induced macrophage osteoclastogenesis and facili‑ tate NF‑κB signaling in bone marrow‑derived macrophages (BMMs) in vitro, the concentration of RANKL is usually too low to evoke bone resorption processes (8,33).”
BackgroundInfluentialCrosstalk between bone and other organs
Yuan, W., & Song, C. (2022) · Medical Review · doi:10.1515/mr-2022-0018 · Cited by 27
“While β1ARsand β3ARswere found tobeweakly expressedor even undetectable in osteoblasts and osteoclasts [96].”
BackgroundIncreased osteogenesis in osteoporotic bone marrow stromal cells by overexpression of leptin
Zheng, B., Jiang, J., Luo, K., Liu, L., Lin, M., Chen, Y., & Yan, F. (2015) · Cell and Tissue Research · doi:10.1007/s00441-015-2167-y · Cited by 24
“…revealed two mechanisms by which leptin regulates bone mass: indirect central inhibition via the sympathetic nervous system (Ducy et al. 2000; Takeda et al. 2002; Elefteriou et al. 2005) and direct peripheral stimulation by acting on cells in the bone marrow (Chen et al. 1996; Hess et al. 2005).”
BackgroundStem cell mobilization by β2-agonists
Cancelas, J. A., & Williams, D. A. (2006) · Nature Medicine · doi:10.1038/nm0306-278 · Cited by 24
Bone Development and Remodeling
Maes, C., & Kronenberg, H. M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-18907-1.00060-3 · Cited by 26
Timing metabolism in cartilage and bone: links between circadian clocks and tissue homeostasis
Gonçalves, C. F., & Meng, Q. (2019) · Journal of Endocrinology · doi:10.1530/joe-19-0256 · Cited by 25
Relationship of Total Body Fat Mass to Bone Area in New Zealand Five-Year-Olds
Goulding, A., Taylor, R. W., Grant, A. M., Murdoch, L., Williams, S., & Taylor, B. J. (2008) · Calcified Tissue International · doi:10.1007/s00223-008-9121-x · Cited by 24
“For example, leptin acts centrally in the brain to lower bone mass via stimulation of sympathetic activity [ 26 ], as well as being anabolic in the peripheral skeleton [27].”
BackgroundSympathetic neural influence on bone metabolism in microgravity (Review)
Mano, T., Nishimura, N., & Iwase, S. (2010) · Acta Physiologica Hungarica · doi:10.1556/aphysiol.97.2010.4.8 · Cited by 24
Mechanical loading of a long bone induces plasticity in sensory input to the central nervous system
Wu, Q. E., Sample, S. J., Baker, T. A., Thomas, C. F., Behan, M., & Muir, P. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.07.078 · Cited by 24
“However, it has been established that the nervous system has important regulatory effects on skeletal metabolism [4,18].”
BackgroundThe Importance of the Gastrointestinal Tract in the Control of Bone Mass Accrual
Karsenty, G., & Gershon, M. D. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.06.011 · Cited by 23
Self-citationRANK/RANKL/OPG pathway is an important for the epigenetic regulation of obesity
Kalkan, R., & Becer, E. (2019) · Molecular Biology Reports · doi:10.1007/s11033-019-04997-z · Cited by 23
Megakaryocyte Diversity in Ontogeny, Functions and Cell-Cell Interactions
Khatib-Massalha, E., & Méndez‐Ferrer, S. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.840044 · Cited by 26
“Additionally, increased sympathetic adrenergic activity has been previously described during aging (105) and might increase osteoporosis and fracture risk by restraining bone formation (106).”
Background
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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