Targeting the central and peripheral nervous system to regulate bone homeostasis: mechanisms and potential therapies

The skeleton is innervated by different types of nerves and receives signaling from the nervous system to maintain homeostasis and facilitate regeneration or repair. Although the role of peripheral nerves and signals in regulating bone homeostasis has been extensively investigated, the intimate relationship between the central nervous system and bone remains less understood, yet it has emerged as a hot topic in the bone field. In this review, we discussed clinical observations and animal studies that elucidate the connection between the nervous system and bone metabolism, either intact or after injury. First, we explored mechanistic studies linking specific brain nuclei with bone homeostasis, including the ventromedial hypothalamus, arcuate nucleus, paraventricular hypothalamic nucleus, amygdala, and locus coeruleus. We then focused on the characteristics of bone innervation and nerve subtypes, such as sensory, sympathetic, and parasympathetic nerves. Moreover, we summarized the molecular features and regulatory functions of these nerves. Finally, we included available translational approaches that utilize nerve function to improve bone homeostasis and promote bone regeneration. Therefore, considering the nervous system within the context of neuromusculoskeletal interactions can deepen our understanding of skeletal homeostasis and repair process, ultimately benefiting future clinical translation.