Nicotinic Acetylcholine Receptors on Osteocytes Impact Bone Mechanoadaptation in a Sexually Dimorphic Manner

Recent evidence suggests acetylcholine has a positive influence on bone mechanotransduction. Osteocytes express components for nicotinic acetylcholine receptors (nAChRs), which are known for mediating calcium signaling and may impact mechanosensitivity. Here, we use novel fluorescent imaging approaches to provide the first evidence of direct interaction between osteocytes and cholinergic nerve fibers in cortical bone in vivo. Moreover, we show that osteocytes are functional targets of cholinergic signaling for bone mechanoadaptation. We report sexually dimorphic patterns in bone structure and mechanobiology based on nAChR function. In females, osteocyte mechanosensitivity was decreased at small force magnitudes and tissue level deficits were recovered with anabolic loading. In males, osteocyte mechanosensitivity was increased in some groups and anabolic loading had very little effect on overall tissue architecture. This work establishes a new signaling paradigm wherein osteocytes interface with cholinergic nerves and bone mechanotransduction is regulated by osteocyte cholinergic signaling in a sexually dimorphic way.