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Conversely, at higher concentrations, NE preferentially Apart from neurotrophic factors, neurotransmitters,
binds to β-adrenergic receptors (β-AR), leading to elevated and neuropeptides, the intricate interplay between glial
RANKL expression and reduced bone formation, thus cells and their associated substances plays a pivotal role
benefiting osteoclast growth and bone resorption. 13,58 in orchestrating bone regeneration processes. Beyond
Moreover, the NE inhibits human BMSC proliferation their traditional roles in neural functions, the glial cells,
through ERK1/2 and PKA phosphorylation pathways. particularly SCs, have emerged as key regulators of bone
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Vasoactive intestinal peptide (VIP), a neuropeptide repair involving a multitude of intricate pathways. SCs
secreted by the sympathetic nerves accompanying with exhibit a remarkable capacity to support nerve regeneration
the NE secretion, exerts a complex regulatory role in bone and augment the proliferation and differentiation of
metabolism (Table 1). While inhibiting BMSC proliferation, osteoblasts following bone injury, thereby contributing
the VIP stimulates osteogenic differentiation in these cells significantly to the restoration of bone integrity.
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by activating diverse signaling cascades involving TGF-β Upon injury, SCs undergo a dynamic phenotypic shift
and BMPs, ultimately promoting bone remodeling and characterized by the downregulation of myelin-associated
regeneration. In contrast, the parasympathetic nervous glycoprotein expression and the upregulation of glial
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system exerts anti-inflammatory effects, preserving fibers and NGF levels, indicative of a myelin-regenerating
bone mass balance by counteracting sympathetic activity phenotype. These cells actively participate in shaping
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and increasing osteoclast apoptosis to reduce bone an anti-inflammatory microenvironment by modulating
resorption. ACh, a primary neurotransmitter of the key signaling pathways such as MAPK, TNF, and Rap1.
13
parasympathetic system, interacts with various receptors Notably, SC-derived exosomes have emerged as promising
to enhance osteoblast proliferation and improve bone mass therapeutic agents for bone repair, as evidenced by their
(Table 1). 61-63 ability to enhance the migration, proliferation, and
differentiation of BMSCs, found by Wu et al. Furthermore,
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On the other hand, peptidergic innervation originating
from the sensory nerves exerts direct regulatory control SC precursors (SCPs) exhibit remarkable plasticity, capable
of differentiation into diverse skeletal progenitor cells
over bone formation through the release of neurogenic and mature osteocytes, thereby contributing to bone
factors, in which some key peptides such as NPY, SP, and regeneration and repair. The paracrine factors, secreted by
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CGRP are involved (Table 1). 60,64 The NPY, known for its
diverse physiological roles, interacts with Y1 receptors on the SCP and directly working on osteoclast differentiation,
play a pivotal role in orchestrating ossification processes,
osteoblasts, influencing cellular functions related to bone modulating inflammatory responses, and influencing
metabolism, and is implicated in modulating the actions vascular development, collectively fostering a conducive
of the NE. 65-67 Experimental evidence suggests that the environment for bone healing. Moreover, recent studies
NPY exerts inhibitory effects on osteoblast functions by have unveiled a neuron-derived small extracellular
reducing cAMP levels, impairing mineralization processes, vesicle (sEV) pathway by which the enriched microRNA
hindering osteoblast differentiation of MSCs, promoting promoted bone regeneration and post-traumatic brain
lipogenesis, and inducing apoptosis in these cells. 65,68,69 In injury. These sEVs, particularly the fibronectin 1 on
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contrast, the SP primarily interacts with the neurokinin their surface, can target key proteins within bone tissues,
1 receptor, stimulating osteoblast activity and promoting facilitating bone healing by modulating the expression
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osteogenesis. Notably, the SP inhibits chondrogenic of critical transcription factors such as FOXO4 and CBL
differentiation and terminal differentiation of chondrocytes proteins through miR-328a-3p and miR-150-5p molecules,
through β-AR signaling pathways during endochondral respectively. 34
ossification. Moreover, the SP facilitates the migration
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of MSCs toward osteogenic niches, also enhancing their 3. Several strategies for building an
proliferation, differentiation, and matrix mineralization in innervated osteogenesis microenvironment
a concentration-dependent manner, thereby accelerating by functional biomaterials
bone remodeling and maturation. 72,73 The CGRP, another
important peptide, influences bone remodeling by As concluded from above, innervation and early neural
regulating local blood flow through vascular actions and development are critical factors for the osteogenesis
direct modulation of intraosseous cellular activities. and bone formation processes that are characterized by
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By binding to calcitonin-like receptor (CLR), the CGRP neuropeptides, neurotransmitters, neurotrophic factors,
inhibits osteoclast generation and differentiation through and other neural cell-derived messengers. Therefore,
intricate signaling pathways, leading to reduced bone in terms of current advances in bone regeneration,
resorption. 75,76 Simultaneously, the CGRP also promotes the integration of specific neuromodulation cues
the migration of MSCs toward osteogenic niches, enhances into biomaterials has attracted interest toward bone
osteogenic differentiation, and inhibits MSC apoptosis. 77-79 organoid construction and refractory bone defect repair.

Volume 1 Issue 1 (2025) 6 doi: 10.36922/OR8294