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

Stephen Gadomski, Claire Fielding, Andrés García-García, Claudia Korn, Chrysa Kapeni, Sadaf Ashraf, Javier Villadiego, Raquel Del Toro, Olivia Domingues, Jeremy N Skepper, Tatiana Michel, Jacques Zimmer, Regine Sendtner, Scott Dillon, Kenneth E S Poole, Gill Holdsworth, Michael Sendtner, Juan J Toledo-Aral, Cosimo De Bari, Andrew W McCaskiePamela G Robey, Simón Méndez-Ferrer*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)528-544.e9
JournalCell Stem Cell
Issue number4
Early online date8 Mar 2022
Publication statusPublished - 7 Apr 2022


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


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