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

Area of Science:

• Neuroscience
• Skeletal Biology
• Autonomic Nervous System

Background:

• The autonomic nervous system regulates bodily functions, but the role of cholinergic signaling in bone homeostasis is unclear.
• Sympathetic noradrenergic fibers are known to reduce bone mass, contrasting with the potential anabolic effects of cholinergic signaling.

Purpose of the Study:

• To investigate the role of cholinergic signaling in bone innervation and its impact on skeletal biology.
• To elucidate the mechanisms underlying sympathetic cholinergic nerve fiber development and function in bone.

Main Methods:

• Analysis of sympathetic nerve fiber plasticity in bone.
• Investigation of neurotrophic factor involvement (GFRα2, NRTN) in nerve-osteocyte interactions.
• Assessment of bone mass and structure following manipulation of cholinergic innervation.
• Evaluation of exercise effects on skeletal cholinergic innervation and bone adaptation.

Main Results:

• A subset of sympathetic nerve fibers undergoes an interleukin-6 (IL-6)-induced cholinergic switch in bone postnatally.
• A neurotrophic dependency via GFRα2/NRTN links sympathetic cholinergic fibers to osteocyte survival and connectivity.
• Bone-lining osteoprogenitors propagate cholinergic signals within the bone marrow.
• Moderate exercise increases bone mass via IL-6-dependent expansion of sympathetic cholinergic fibers.
• Loss of cholinergic innervation leads to osteopenia and impaired exercise adaptation.

Conclusions:

• A cholinergic neuro-osteocyte interface regulates skeletogenesis and bone turnover.
• Cholinergic innervation is essential for osteocyte survival, function, and skeletal adaptation.
• This pathway mediates bone-anabolic effects, particularly in response to exercise.