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Figure 2. Schematic illustration of the skeletal nerve functions in bone tissue development and regeneration. Part of the graphic materials used in this
schematic illustration were obtained from Figdraw.
Abbreviations: 5-HT: Serotonin; BDNF: Brain-derived neurotrophic factor; CGRP: Calcitonin gene-related peptide; CNS: Central nervous system;
DRG: Dorsal root ganglion; NGF: Nerve growth factor; NPY: Neuropeptide Y; NT-3: Neurotrophin-3; PNS: Peripheral nervous system; SP: Substance P;
VIP: Vasoactive intestinal peptide.

osteogenic signaling pathways are involved for the DRG facilitating the sensory nerve and inferior alveolar nerve
neurons to respond to bone injury with the secretion recovery and indirectly promoting bone regeneration. 46,47
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of various neuroskeletal regulatory factors. The DRG Similarly, the BDNF, primarily found in the brain, has
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neurons can be sensitized by the macrophage-neuron- also been implicated in influencing bone healing processes
osteoblast axis to participate in regulating bone metabolism (Table 1). Activation of the ERK1/2 and AKT signaling
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and homeostasis through CGRP secretion for stimulating pathways through the TrkB receptor by BDNF has
vascularized bone neogenesis. 36 been shown to increase integrin β1 expression, thereby
promoting the proliferation and differentiation of human
2.3. The main neuro-modulatory pathways of bone BMSCs, amplifying RANKL production, and ultimately
regeneration
promoting osteoblast growth. Moreover, the NT-3,
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The CNS and PNS play a fundamental role in regulating binding with its receptor TrkC, induces the upregulation of
skeletal metabolism through different neuromodulation BMP-2 and TGF-β1 expression, facilitating the osteogenic
pathways. CNS-related pathways and neurotransmitters differentiation of rat BMSCs (Table 1). 51
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can maintain a delicate balance between bone formation
and absorption. For example, leptin, a hormone secreted by Furthermore, Sema3A, a guidance molecule in axonal
adipocytes, interacts with the hypothalamus to trigger the pathfinding, has been identified as another key regulator
release of NE, which activates β2 receptors on osteoblasts, of bone resorption and formation, coupling osteoblasts and
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interfering with bone mass regulation and suppressing osteoclasts during bone metabolism (Table 1). The binding
bone formation (Table 1). 38,39 In addition, 5-HT can of Sema3A to the Nrp-1 receptor can activate the Wnt/β-
modulate sympathetic nerve activity, indirectly impacting catenin signaling pathway in osteoblasts and enhance
bone resorption and promoting bone formation (Table 1). 40 osteogenic differentiation of BMSCs with osteogenesis-
related gene expression. Moreover, the neuron-derived
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Neurotrophic factors, such as NGF, BDNF, and Sema3A not only promotes normal nervous system
neurotrophin-3 (NT-3), play critical roles in the development but also participates in regulating vascular
development of diverse nerve cells in both the CNS and invasion, further contributing to bone formation. 54,55
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PNS (Table 1). Among these factors, the NGF has been
demonstrated to facilitate osteoblast proliferation and The autonomic nervous system exerts significant
differentiation and inhibit their apoptosis, contributing to influence on bone metabolism, precursor cell differentiation,
osteoblast generation (Table 1). 33,42,43 Furthermore, the NGF extracellular matrix mineralization, and tissue
binds to the TrkA receptor, enhancing the survival rate and remodeling processes, primarily through different signal
regenerative capacity of BMSCs, and upregulating the transduction pathways regulated by neurotransmitters and
44
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expression of transforming growth factor beta (TGF-β) neuropeptides. Sympathetic innervation, characterized by
and bone morphogenetic protein 9 (BMP-9) to promote the release of NE, exerts dual effects on bone homeostasis
osteogenic differentiation. Studies have indicated that (Table 1). By activating α-adrenergic receptors at low
45
the NGF can induce load-induced nerve sprouting in concentrations, the NE enhances DNA synthesis in the
a rabbit mandibular distraction osteogenesis model, rat BMSCs, thereby promoting osteoblast proliferation.
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Volume 1 Issue 1 (2025) 4 doi: 10.36922/OR8294