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

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-a2 (GFRa2) 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.

Automated summary

The autonomic nervous system plays a crucial role in regulating homeostasis and response to stress. This study reveals the involvement of cholinergic signaling in bone development and function through the interaction between sympathetic cholinergic nerve fibers and osteocytes. Cholinergic innervation is important for osteocyte survival and connectivity, and moderate exercise can enhance bone development by increasing sympathetic cholinergic nerve fibers. Loss of cholinergic skeletal innervation leads to osteopenia and impaired skeletal adaptation to exercise.