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

• Published in: Cell stem cell 2022-04, Vol.29 (4), p.528-544.e9
• Main 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 E.S., Holdsworth, Gill, Sendtner, Michael, Toledo-Aral, Juan J., De Bari, Cosimo, McCaskie, Andrew W., Robey, Pamela G., Méndez-Ferrer, Simón
• Format: Article
• Language: English
• Subjects: anabolic; autonomic; bone; cholinergic; Cholinergic Agents; Cholinergic Fibers; development; exercise; Glial Cell Line-Derived Neurotrophic Factor Receptors - physiology; Interleukin-6; neuroskeletal; osteocyte; Osteogenesis; skeletal; sympathetic
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2022.02.008

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. [Display omitted] •IL-6 induces a cholinergic switch of sympathetic neurons contacting bone postnatally•Neurturin-GFRα2 pathway maintains cholinergic neuro-osteocyte coupling and survival•Bone-lining osteoprogenitors amplify cholinergic signaling in bone and bone marrow•IL-6-induced cholinergic signaling has a bone-anabolic effect during moderate exercise Gadomski et al. describe a neuro-osteocyte interface whereby sympathetic cholinergic neurons support bone-embedded osteocytes through the GFRα2 neurotrophic pathway. Developmentally, these sympathetic neurons undergo a neurotransmitter switch from adrenergic to cholinergic—a process that is induced by interleukin-6 and is dynamically enhanced by physical activity to increase bone mass.