Neural regulation of bone: from central neural circuits to peripheral innervation of the skeletal stem cell niche

Abstract The nervous system has emerged as a multi-scale regulator of bone biology, integrating central neural circuits with peripheral innervation to control skeletal homeostasis and repair. While bone remodeling is classically described as being governed by coupling between bone formation and resorption, neural signaling provides an additional hierarchical layer that links organism-level cues to local skeletal stem/progenitor cell niches. This review presents a mechanistic framework for the neuro–bone regulatory network across three hierarchical levels. First, we examine central regulation, in which hypothalamic circuits integrate hormonal and metabolic signals via circumventricular organs to modulate endocrine outputs such as parathyroid hormone (PTH), thereby establishing circadian rhythms and systemic control of bone metabolism. Second, we analyze peripheral neural communication, where sensory inputs triggered by injury or inflammation, along with autonomic efferent signaling, including β-adrenergic pathways, directly influence osteolineage and stromal cells. These signals recalibrate cellular metabolic states, differentiation programs, and regenerative responses, linking pain perception with tissue repair mechanisms. Third, we investigate the bone marrow niche, where distinct subtypes of nerve fibers release a diverse array of neurotransmitters and or neuromodulators that shape the microenvironment of skeletal stem and progenitor cells (SSPCs) as well as downstream osteoprogenitors, thereby regulating proliferation, lineage commitment, and quiescence. Collectively, these findings delineate an integrated model of neural regulation of bone spanning central, peripheral, and local niche levels, providing a foundation for testable hypotheses in neuro-osteobiology.