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Table 1. Key molecules, biological processes, and corresponding signaling pathways of nerve–bone crosstalk
Neuroactive Receptors Processes Outcomes Signaling References
molecules pathways
Leptin Hypothalamus Upregulating osteoblast β2 Interfering with bone mass Wnt 13,38,85,86
receptor and BMSC leptin regulation; suppressing bone
receptor expression; enhancing formation.
the NE level in the hypothalamus.
5-HT Sympathetic nerve Suppressing sympathetic nerve Inhibiting bone resorption and -- 40
activity. stimulating bone formation.
Sema3A Neuropilin-1 (Nrp-1) Activating RANKL receptor Regulating bone resorption and Wnt/β-catenin 52,53,87
for promoting osteogenic gene bone formation; participating in
expression of osteoblasts and neural and vascular formation.
BMSCs.
NGF TrkA Upregulating TGF-β, BMP-9, Innervation, vascularization, NGF/TrkA 43-47
and VEGF gene expression; and bone regeneration.
suppressing SMAD and
p38-MAPK expression;
promoting BMSC survival
and osteoblast differentiation;
restoring sensory neuron activity.
BDNF TrkB Increasing integrin β1 expression; Bone fracture healing and bone ERK1/2, Akt 50,88
promoting BMSC proliferation regeneration.
and osteoblast differentiation.
NT-3 TrkC Increasing expression of BMP-2 Enhanced osteogenic ERK1/2, Akt 51
and TGF-β1. differentiation of BMSCs.
NE Adrenergic receptors Activating α-adrenergic receptors Inhibition of bone resorption ERK1/2, PKA, 13,59,89-91
(α-AR and β-AR) (α-AR) at low NE levels to and acceleration of bone RANKL/
enhance BMSC proliferation; formation. RANK/OPG
inhibiting osteoclast growth by
reducing β-AR at high NE level.
ACh Muscarinic receptor Promoting osteoblast Bone mass regulation and -- 61-63
(mAChRs) and nicotinic proliferation. osteocyte amplification.
receptor (nAChRs)
VIP Intestinal peptide Decreasing BMSC proliferation; Maintaining bone metabolism TGF-β, BMP, 92
receptor type 1 (VPAC1) promoting osteoblast and accelerating bone SMAD
differentiation and osteoclast regeneration.
apoptosis.
NPY G-protein coupled Downregulating osteogenic gene Interfering bone metabolism. -- 65,68-69
receptor (GPCR) expression by reducing cAMP and
NE levels.
SP Neurokinin-1 receptor Promoting BMSC migration, Regulation of bone formation β-adrenergic 70-72,93-95
(NK1R) osteoblast differentiation, and and bone resorption. receptor (AR),
matrix mineralization. BMP, ERK1/2,
Wnt/β-catenin
CGRP Calcitonin receptor-like Inhibiting osteoclast growth Bone remodeling and reduction Wnt/β-catenin, 75,76,77-79
receptor (CLR) and promoting osteoblast of bone resorption. PPARγ,
differentiation. p38-MAPK,
Hippo/Yap,
RANKL/OPG
Note: This table provides a comprehensive overview of the key molecules, dynamic processes, and corresponding signaling pathways of nerve–bone
crosstalk. Each entry provides detailed information regarding the specific neurotransmitters or growth factors, the corresponding action sites or
receptors, the biological processes experienced, the outcomes achieved, the signaling pathways involved, and relevant citations for further reference.
Abbreviations: ACh: Acetylcholine; AR: Adrenergic receptor; BDNF: Brain-derived neurotrophic factor; BMP-2: Bone morphogenetic protein 2;
BMP-9: Bone morphogenetic protein 9; BMSCs: Bone marrow-derived mesenchymal stem cells; CGRP: Calcitonin gene-related peptide; 5-HT:
Serotonin; NE: Norepinephrine; NGF: Nerve growth factor; NPY: Neuropeptide Y; Nrp-1: Neuropilin-1; NT-3: Neurotrophin-3; Sema3A: Semaphorin
3A; SP: Substance P; TGF-β: Transforming growth factor beta; Trk: Tyrosine kinase; VEGF: Vascular endothelial growth factor;
VIP: Vasoactive intestinal peptide.

Volume 1 Issue 1 (2025) 5 doi: 10.36922/OR8294