A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise

Stephen Gadomski, Claire Fielding , Andrés García-García, Claudia Korn, Sadaf Ashraf, Javier Villadiego, Raquel del Toro, Olivia Domingues, Jeremy N. Skepper, Tatiana Michel, Jacques Zimmer, Regine Sendtner, Scott Dillon, Kenneth Poole, Gill Holdsworth, Michael Sendtner, Juan J. Toledo-Aral, Cosimo De Bari, Andrew W. McCaskie, Pamela G RobeySimón Méndez-Ferrer* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)
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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 (GFR2) 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.
Original languageEnglish
Pages (from-to)528-544.e9
Number of pages17
JournalCell Stem Cell
Issue number4
Early online date10 Mar 2022
Publication statusPublished - 7 Apr 2022

Bibliographical note

We thank the Weizmann Institute of Science (Israel) for data discussion (T. Lapidot) and for providing TACE inhibitor (I. Sagi, A. Hanuna, and O. Kollet); E. Chu (NIH/NIAMS) and V. Kram (NIH/NIDCR) for assistance with μCT analysis and dynamic histomorphometry data, S. Ozanne (University of Cambridge) for treadmill and A. Horton and A. Davies (Cardiff University) for demonstrating SGC culture protocol; M. Airaksinen for Gfra2−/− mice; E. Khatib-Massalha, E. Grockowiak, Z. Fang, and other members of the S.M.-F. group for support and data discussion; A.R. Green and M. Birch (University of Cambridge), A. Pascual and J. López-Barneo (Universidad de Sevilla) for data discussion; P. Chacón-Fernández, N. Suárez-Luna, F.J. Martín, and C.O. Pintado, in memoriam, (Centro de Experimentación Animal; CEA, Universidad de Sevilla), D. Pask, T. Hamilton (University of Cambridge), the Central Biomedical Services, and Cambridge NIHR BRC Cell Phenotyping Hub for technical assistance; Genentech for providing tocilizumab; UCB Pharma for providing Scl-Ab r13c7. S.G. was supported by the NIH-OXCAM Program and the Gates Cambridge Trust. A.G.G. received fellowships from Ramón Areces and La Caixa Foundations. C.K. was supported by Marie Curie Career Integration grant H2020-MSCA-IF-2015-70841. M.S. and R.S. were supported by DFG, Se 697/7-1 and BMBF through the EnergI consortium TP6. J.V. and J.J.T.-A. were supported by Instituto de Salud Carlos III (PI12/02574), Junta de Andalucia (P12-CTS-2739), and, together with S.M.-F., by Red TerCel (ISCIII-Spanish Cell Therapy Network). S.A. and C.D.B. were supported by Versus Arthritis grant 21156. A.W.M. received funding from Versus Arthritis (21156). P.G.R. and S.G. were supported by the DIR, NIDCR, a part of the IRP, NIH, and DHHS (1ZIADE000380). K.E.S.P. acknowledges the support of the Cambridge NIHR Biomedical Research Centre. This work was supported by core support grants from MRC to the Cambridge Stem Cell Institute; National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 research (ERC-2014-CoG-648765), MRC-AMED grant MR/V005421/1, and a Programme Foundation Award (C61367/A26670) from Cancer Research UK to S.M.-F. This research was funded in part by the Wellcome Trust (203151/Z/16/Z). For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

Data Availability Statement

Microscopy data reported in this paper will be shared by the lead contact upon request.
This paper does not report original code.
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.


  • cholinergic
  • sympathetic
  • osteocyte
  • autonomic
  • development
  • skeletal
  • bone
  • exercise
  • neuroskeletal
  • anabolic


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