Gadomski, Stephen, Fielding, Claire, García-García, Andrés, Korn, Claudia, Kapeni, Chrysa, Ashraf, Sadaf, Villadiego, Javier, del Toro, Raquel, Domingues, Olivia, Skepper, Jeremy N., and others. (2022) A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise. Cell Stem Cell, 29 (4). pp. 528-544. ISSN 1934-5909. (doi:10.1016/j.stem.2022.02.008) (KAR id:109971)
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Language: English 
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| Official URL: https://doi.org/10.1016/j.stem.2022.02.008 |
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Abstract
The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone. A neurotrophic dependency mediated through GDNF-family receptor-α2 (GFRα2) and its ligand, neurturin (NRTN), is established between sympathetic cholinergic fibers and bone-embedded osteocytes, which require cholinergic innervation for their survival and connectivity. Bone-lining osteoprogenitors amplify and propagate cholinergic signals in the bone marrow (BM). Moderate exercise augments trabecular bone partly through an IL-6-dependent expansion of sympathetic cholinergic nerve fibers. Consequently, loss of cholinergic skeletal innervation reduces osteocyte survival and function, causing osteopenia and impaired skeletal adaptation to moderate exercise. These results uncover a cholinergic neuro-osteocyte interface that regulates skeletogenesis and skeletal turnover through bone-anabolic effects.
| Item Type: | Article |
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| DOI/Identification number: | 10.1016/j.stem.2022.02.008 |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology |
| Institutional Unit: | Schools > Medway School of Pharmacy |
| Former Institutional Unit: |
There are no former institutional units.
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| Funders: | Versus Arthritis (https://ror.org/02jkpm469) |
| Depositing User: | Sadaf Ashraf |
| Date Deposited: | 23 May 2025 15:18 UTC |
| Last Modified: | 22 Jul 2025 09:23 UTC |
| Resource URI: | https://kar.kent.ac.uk/id/eprint/109971 (The current URI for this page, for reference purposes) |
University of Kent Author Information
Ashraf, Sadaf.
| Creator's ORCID: |
 https://orcid.org/0000-0001-5592-9122
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