A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise.
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Authors
Gadomski, Stephen
Fielding, Claire
García-García, Andrés
Korn, Claudia
Kapeni, Chrysa
Ashraf, Sadaf
Villadiego, Javier
Toro, Raquel Del
Domingues, Olivia
Skepper, Jeremy N
Michel, Tatiana
Zimmer, Jacques
Sendtner, Regine
Dillon, Scott
Poole, Kenneth ES
Holdsworth, Gill
Sendtner, Michael
Toledo-Aral, Juan J
De Bari, Cosimo
McCaskie, Andrew W
Robey, Pamela G
Méndez-Ferrer, Simón
Publication Date
2022-04-07Journal Title
Cell Stem Cell
ISSN
1934-5909
Publisher
Elsevier BV
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Gadomski, S., Fielding, C., García-García, A., Korn, C., Kapeni, C., Ashraf, S., Villadiego, J., et al. (2022). A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise.. Cell Stem Cell https://doi.org/10.1016/j.stem.2022.02.008
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.
Sponsorship
European Research Council (648765)
NHS Blood and Transplant (NHSBT)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (708411)
Cancer Research UK (C61367/A26670)
MRC (MR/V005421/1)
Wellcome Trust (203151/Z/16/Z)
ARTHRITIS RESEARCH UK (21156)
Identifiers
External DOI: https://doi.org/10.1016/j.stem.2022.02.008
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334022
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