A Procedural Overview of the Involvement of Small Molecules in the Nervous System in the Regulation of Bone Healing

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Date 2025 Feb 5

PMID 39906525

Authors

Xuyan Wei

Mucong Li

Jiaqian You

Jiaxin Luo

Jingjie Zhai

Jiameng Zhang

Jian Feng

Hanchi Wang

Yanmin Zhou

Affiliations

Soon will be listed here.

Abstract

Clinically, a multitude of factors can contribute to the development of bone defects. In the process of bone healing, the nervous system plays a vital role in bone regeneration. Small molecules from the nervous system, such as neurotrophic factors and neuropeptides, have been found to stimulate osteoblast proliferation and differentiation by activating signaling pathways associated with bone calcification and angiogenesis. These small molecules play a crucial regulatory role at various stages of bone healing. The systematic release mechanism of small molecules within the nervous system through diverse bone tissue engineering materials holds significant clinical implications for the controlled regulation of the bone healing process. This review provides an overview of the involvement of various nervous system small molecules at different stages of bone healing and discusses their regulatory mechanisms, aiming to establish a theoretical foundation for programmed regulation in bone regeneration and design of replacement materials in bone tissue engineering.

References

Safari B, Davaran S, Aghanejad A . Osteogenic potential of the growth factors and bioactive molecules in bone regeneration. Int J Biol Macromol. 2021; 175:544-557. DOI: 10.1016/j.ijbiomac.2021.02.052. View

Peng Y, Wu S, Li Y, Crane J . Type H blood vessels in bone modeling and remodeling. Theranostics. 2020; 10(1):426-436. PMC: 6929606. DOI: 10.7150/thno.34126. View

Fitzpatrick V, Martin-Moldes Z, Deck A, Torres-Sanchez R, Valat A, Cairns D . Functionalized 3D-printed silk-hydroxyapatite scaffolds for enhanced bone regeneration with innervation and vascularization. Biomaterials. 2021; 276:120995. PMC: 8408341. DOI: 10.1016/j.biomaterials.2021.120995. View

Pang J, Guo H, Ding D, Wu Y, Zhao Y, Gu X . Changes of mesenchymal stromal cells mobilization and bone turnover in an experimental bone fracture model in ovariectomized mice. Int J Clin Exp Pathol. 2015; 8(9):10228-38. PMC: 4637546. View

Niedzwiedzki T, Filipowska J . Bone remodeling in the context of cellular and systemic regulation: the role of osteocytes and the nervous system. J Mol Endocrinol. 2015; 55(2):R23-36. DOI: 10.1530/JME-15-0067. View

Tabarowski Z, Felten S . Noradrenergic and peptidergic innervation of the mouse femur bone marrow. Acta Histochem. 1996; 98(4):453-7. DOI: 10.1016/S0065-1281(96)80013-4. View

Rivera K, Russo F, Boileau R, Tomlinson R, Miclau T, Marcucio R . Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion. Sci Rep. 2020; 10(1):22241. PMC: 7747641. DOI: 10.1038/s41598-020-78983-y. View

Al-Baadani M, Xu L, Cai K, Ru Yie K, Shen Y, Al-Bishari A . Preparation of co-electrospinning membrane loaded with simvastatin and substance P to accelerate bone regeneration by promoting cell homing, angiogenesis and osteogenesis. Mater Today Bio. 2023; 21:100692. PMC: 10338360. DOI: 10.1016/j.mtbio.2023.100692. View

Colucci-DAmato L, Speranza L, Volpicelli F . Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer. Int J Mol Sci. 2020; 21(20). PMC: 7589016. DOI: 10.3390/ijms21207777. View

10.

Teixeira L, Sousa D, Nunes A, Sousa M, Herzog H, Lamghari M . NPY revealed as a critical modulator of osteoblast function in vitro: new insights into the role of Y1 and Y2 receptors. J Cell Biochem. 2009; 107(5):908-16. DOI: 10.1002/jcb.22194. View

11.

Siddiqui J, Partridge N . Physiological Bone Remodeling: Systemic Regulation and Growth Factor Involvement. Physiology (Bethesda). 2016; 31(3):233-45. PMC: 6734079. DOI: 10.1152/physiol.00061.2014. View

12.

Maisonpierre P, Belluscio L, Squinto S, Ip N, Furth M, Lindsay R . Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science. 1990; 247(4949 Pt 1):1446-51. DOI: 10.1126/science.247.4949.1446. View

13.

Wang Z, Zou C, Zhan X, Li X, Ghen G, Gao J . Application of double plate fixation combined with Masquelet technique for large segmental bone defects of distal tibia: a retrospective study and literature review. BMC Surg. 2024; 24(1):103. PMC: 11007926. DOI: 10.1186/s12893-024-02396-1. View

14.

Cross M, Claesson-Welsh L . FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci. 2001; 22(4):201-7. DOI: 10.1016/s0165-6147(00)01676-x. View

15.

Goadsby P, Edvinsson L, Ekman R . Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990; 28(2):183-7. DOI: 10.1002/ana.410280213. View

16.

Cheret J, Lebonvallet N, Carre J, Misery L, Le Gall-Ianotto C . Role of neuropeptides, neurotrophins, and neurohormones in skin wound healing. Wound Repair Regen. 2013; 21(6):772-88. DOI: 10.1111/wrr.12101. View

17.

Xiong J, Liao J, Liu X, Zhang Z, Adams J, Pacifici R . A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin. Nat Commun. 2022; 13(1):4820. PMC: 9381595. DOI: 10.1038/s41467-022-32435-5. View

18.

Mercado-Pagan A, Stahl A, Shanjani Y, Yang Y . Vascularization in bone tissue engineering constructs. Ann Biomed Eng. 2015; 43(3):718-29. PMC: 4979539. DOI: 10.1007/s10439-015-1253-3. View

19.

Fang H, Zhu D, Yang Q, Chen Y, Zhang C, Gao J . Emerging zero-dimensional to four-dimensional biomaterials for bone regeneration. J Nanobiotechnology. 2022; 20(1):26. PMC: 8740479. DOI: 10.1186/s12951-021-01228-1. View

20.

Juhasz T, Szentleleky E, Somogyi C, Takacs R, Dobrosi N, Engler M . Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Pathway Is Induced by Mechanical Load and Reduces the Activity of Hedgehog Signaling in Chondrogenic Micromass Cell Cultures. Int J Mol Sci. 2015; 16(8):17344-67. PMC: 4581197. DOI: 10.3390/ijms160817344. View