It was believed that cytokines and hormones are main regulators of bone remodeling. However, this view has been challenged. Organ network has been shown to play a major role in homeostasis, recently. Bone is not the exception.
Clinically, it is well known that head trauma accelerates fracture healing. Advances in molecular genetics revealed that neurons and neuropeptides, including sympathetic nervous system, are intimately involved in bone remodeling.
Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that plays an important role in axon guidance. Previous studies have demonstrated that Sema3A is an osteo-anabolic autocrine and, accordingly, Sema3A-KO mice develop a low bone mass due to decreased bone formation. However, recently, we demonstrated that mice lacking Sema3A in neurons had low bone mass similar to Sema3A-KO mice, indicating that neuron-derived Sema3A is responsible for the bone abnormalities independent of the local effect of Sema3A in bone. Indeed, sensory innervations of trabecular bone were significantly decreased in neuron-specific Sema3A-KO. Moreover, ablating sensory nerves decreased bone mass in WT mice, whereas it did not deteriorate low bone mass phenotype in neuron specific Sema3A-KO mice, further indicating the essential role of sensory nervous system in normal bone homeostasis. Thus, we demonstrated that sensory nervous system is also a critical regulator of bone remodeling.