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

Abstract

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.

Keywords: Bone homeostasis; Brain nuclei; Central nervous system; Osteoporosis; Peripheral nerve fiber.

Fig. 1

Control of bone metabolism by central nervous system regions. Brain nuclei can control different aspects of the body and bone homeostasis. These nuclei are associated with some very fundamental functions of the body, including fluid and electrolyte control, circulation function, general arousal level, etc. These nuclei can also regulate bone mass by altering the bone-regulating hormone (PTH, gonadal hormone, growth factor, and epinephrine) level or response to the hormone. These brain nuclei may also send nerve projections to bone and regulate bone homeostasis via the release of neurotransmitters or neuropeptides. SFO subfornical organ, LC locus coeruleus, BLA basolateral complex of the amygdala, PVN paraventricular hypothalamic nucleus, POA preoptic area, ARC arcuate nucleus, VMH ventromedial hypothalamus, RPa raphe pallidus nucleus, HPA hypothalamic–pituitary–adrenal, PTH parathyroid hormone, GHRH growth hormone-releasing hormone, GH growth hormone, IGF-1 insulin-like growth factor-1

Fig. 2

Key biomarkers and regulatory factors released from the nerve terminal in the bone. For sympathetic nerve terminals, tyrosine hydroxylase (TH) is the rate-limiting enzyme for norepinephrine (NE) synthesis and is commonly used as a marker for the sympathetic nerve. For parasympathetic nerve terminals, acetylcholinesterase (AChE) is essential in producing acetylcholine (Ach). Several neuropeptides (BDNF, CGRP, NGF, and SP) can be released from sensory nerve terminals and act on their receptor on target organs. VIP vasoactive intestinal peptide, NPY neuropeptide Y, BDNF brain-derived neurotrophic factor, NGF nerve growth factor, CGRP calcitonin gene-related peptide, SP substance P, VPAC vasoactive intestinal peptide receptor, BchE butyrylcholinesterase, Y1R neuropeptide Y1 receptor, TrkA tropomyosin receptor kinase A, TrkB tropomyosin receptor kinase B, RAMP receptor activity modifying protein, NKIR neurokinin 1 receptor, Calcrl calcitonin receptor like receptor