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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Gadomski, Stephen 
Fielding, Claire 
García-García, Andrés 
Korn, Claudia 
Kapeni, Chrysa 

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.

Description

Keywords

anabolic, autonomic, bone, cholinergic, development, exercise, neuroskeletal, osteocyte, skeletal, sympathetic, Cholinergic Agents, Cholinergic Fibers, Glial Cell Line-Derived Neurotrophic Factor Receptors, Interleukin-6, Osteogenesis

Journal Title

Cell Stem Cell

Conference Name

Journal ISSN

1934-5909
1875-9777

Volume Title

Publisher

Elsevier BV
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)
Medical Research Council (MC_PC_17230)