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REVIEW ARTICLE

The neuro-vascular-osteo regulatory network and the brain-bone axis: Pathological mechanisms, clinical manifestations, and novel targeted therapies in neurogenic bone diseases

Zifeng Wang† ,  Ying Xu† ,  Jian Wang*
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1 Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
†These authors contributed equally to this work.
OTE, 026100005 https://doi.org/10.36922/OTE026100005
Received: 4 March 2026 | Revised: 12 April 2026 | Accepted: 29 April 2026 | Published online: 15 May 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Neurogenic bone diseases, including sublesional bone loss and neurogenic heterotopic ossification, are severe complications following central nervous system (CNS) trauma or neurodegeneration. Despite rising incidence, research on the neuro‑vascular‑osteo regulatory network remains largely preclinical, and clinical management lacks consensus. Current interventions involve conventional antiresorptive agents or delayed surgical excision, yet their efficacy is often inadequate. Recent advances in spatial transcriptomics, novel neuropeptides (secretoneurin, spexin), and skeletal interoception have illuminated the brain‑bone axis’s bidirectional mechanisms. Emerging studies indicate that targeting this axis—via NPY1R antagonists, repurposed β‑blockers, or Schwann cell‑seeded piezoelectric biomaterials—can restore bone homeostasis. This review discusses pathological mechanisms, clinical biomarkers, and the translation of targeted therapies and engineered scaffolds for managing neurogenic bone diseases.

Keywords
Brain-bone axis
Neurogenic bone diseases
Skeletal interoception
Neurogenic heterotopic ossification
Neuro-vascular niche
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
References
  1. Chen M, Li Y, Huang X, et al. Skeleton-vasculature chain reaction: a novel insight into the mystery of homeostasis. Bone Res. 2021;9(1):21. doi: 10.1038/s41413-021-00138-0

 

  1. Liang TZ, Jin ZY, Lin YJ, et al. Targeting the central and peripheral nervous system to regulate bone homeostasis: mechanisms and potential therapies. Military Med Res. 2025;12(1):13. doi: 10.1186/s40779-025-00600-8

 

  1. Zhang Z, Wang F, Huang X, et al. Engineered Sensory Nerve Guides Self‐Adaptive Bone Healing via NGF‐TrkA Signaling Pathway. Adv Sci. 2023;10(10):2206155. doi: 10.1002/advs.202206155

 

  1. Elefteriou F. Impact of the Autonomic Nervous System on the Skeleton. Physiol Rev. 2018;98(3):1083-1112. doi: 10.1152/physrev.00014.2017

 

  1. Bessy T, Itkin T, Passaro D. Bioengineering the Bone Marrow Vascular Niche. Front Cell Dev Biol. 2021;9:645496. doi: 10.3389/fcell.2021.645496

 

  1. Massaccesi L, Corsi Romanelli MM, Galliera E. Brain–Bone Axis in Physiological and Pathological Conditions. IJMS. 2025;26(19):9822. doi: 10.3390/ijms26199822

 

  1. Zhao Y, Peng X, Wang Q, et al. Crosstalk Between the Neuroendocrine System and Bone Homeostasis. Endocr Rev. 2024;45(1):95-124. doi: 10.1210/endrev/bnad025

 

  1. Zhao H, Feng J, Seidel K, et al. Secretion of Shh by a Neurovascular Bundle Niche Supports Mesenchymal Stem Cell Homeostasis in the Adult Mouse Incisor. Cell Stem Cell. 2014;14(2):160-173. doi: 10.1016/j.stem.2013.12.013

 

  1. Rindone AN, Liu X, Farhat S, et al. Quantitative 3D imaging of the cranial microvascular environment at single-cell resolution. Nat Commun. 2021;12(1):6219. doi: 10.1038/s41467-021-26455-w

 

  1. Lin W, Li Y, Qiu C, et al. Mapping the spatial atlas of the human bone tissue integrating spatial and single-cell transcriptomics. Nucleic Acids Res. 2025;53(2):gkae1298. doi: 10.1093/nar/gkae1298

 

  1. Liu Y, Da W, Xu MJ, et al. Single-cell transcriptomics reveals novel chondrocyte and osteoblast subtypes and their role in knee osteoarthritis pathogenesis. Sig Transduct Target Ther. 2025;10(1):40. doi: 10.1038/s41392-025-02136-8

 

  1. Zhao H, Chai Y. Stem Cells in Teeth and Craniofacial Bones. J Dent Res. 2015;94(11):1495-1501. doi: 10.1177/0022034515603972

 

  1. Kim BJ, Lee YS, Lee SY, et al. Osteoclast-secreted SLIT3 coordinates bone resorption and formation. J Clin Invest. 2018;128(4):1429-1441. doi: 10.1172/JCI91086

 

  1. Shin B, Kupferman J, Schmidt E, Polleux F, Delany AM, Lee SK. Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3. J Bone Mineral Res. 2020;35(4):789-800. doi: 10.1002/jbmr.3945

 

  1. Blockus H, Chédotal A. Slit-Robo signaling. Development. 2016;143(17):3037-3044. doi: 10.1242/dev.132829

 

  1. Wang F, Zhang F, Lin B, Xiao W, Wang X, Wang N. Sarsasapogenin stimulates angiogenesis and osteogenesis coupling to treat estrogen deficiency-induced osteoporosis by activating the GPX4/SLIT3/ROBO1 axis. Phytomedicine. 2025;136:156297. doi: 10.1016/j.phymed.2024.156297

 

  1. Takeda S, Elefteriou F, Levasseur R, et al. Leptin Regulates Bone Formation via the Sympathetic Nervous System. Cell. 2002;111(3):305-317. doi: 10.1016/S0092-8674(02)01049-8

 

  1. Xie W, Li F, Han Y, et al. Neuropeptide Y1 receptor antagonist promotes osteoporosis and microdamage repair and enhances osteogenic differentiation of bone marrow stem cells via cAMP/PKA/CREB pathway. Aging. 2020;12(9):8120-8136. doi: 10.18632/aging.103129

 

  1. Wang Z, Han X, Xu J, et al. Hypothalamus Regulates Anabolic Metabolism of Articular Cartilage Superficial Chondrocytes through PGE2 Skeletal Interoception. Adv Sci. 2025;12(19):2501039. doi: 10.1002/advs.202501039

 

  1. Bai L, Li J, Li G, Zhou D, Su J, Liu C. Skeletal interoception and prospective application in biomaterials for bone regeneration. Bone Res. 2025;13(1):1. doi: 10.1038/s41413-024-00378-w

 

  1. Murthy SE, Loud MC, Daou I, et al. The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. Sci Transl Med. 2018;10(462):eaat9897. doi: 10.1126/scitranslmed.aat9897

 

  1. Lv X, Gao F, Cao X. Skeletal interoception in bone homeostasis and pain. Cell Metab. 2022;34(12):1914-1931. doi: 10.1016/j.cmet.2022.09.025

 

  1. Guo Q, Chen N, Patel K, Wan M, Zheng J, Cao X. Unloading‐ Induced Skeletal Interoception Alters Hypothalamic Signaling to Promote Bone Loss and Fat Metabolism. Adv Sci. 2023;10(35):2305042. doi: 10.1002/advs.202305042

 

  1. Salem Ahim S, Aghaei S, Banei F, et al. Brain-gut-bone axis; a review of the association between gut microbiota and osteoporosis. J Parathyr Dis. 2025;13:e13307. doi: 10.34172/jpd.2025.13307

 

  1. Tong L, Yu H, Huang X, et al. Current understanding of osteoarthritis pathogenesis and relevant new approaches. Bone Res. 2022;10(1):60. doi: 10.1038/s41413-022-00226-9

 

  1. Tretter BL, Dolbow DR, Ooi V, et al. Neurogenic Aging After Spinal Cord Injury: Highlighting the Unique Characteristics of Aging After Spinal Cord Injury. J Clin Med. 2024;13(23):7197. doi: 10.3390/jcm13237197

 

  1. Guízar-Sahagún G, Grijalva I, Franco-Bourland RE, Madrazo I. Aging with spinal cord injury: A narrative review of consequences and challenges. Ageing Res Rev. 2023;90:102020. doi: 10.1016/j.arr.2023.102020

 

  1. Antoniou G, Benetos IS, Vlamis J, Pneumaticos SG. Bone Mineral Density Post a Spinal Cord Injury: A Review of the Current Literature Guidelines. Cureus. 2022;14(3):e23434. doi: 10.7759/cureus.23434

 

  1. Brady RD, Shultz SR, McDonald SJ, O’Brien TJ. Neurological heterotopic ossification: Current understanding and future directions. Bone. 2018;109:35-42. doi: 10.1016/j.bone.2017.05.015

 

  1. Tseng HW, Kulina I, Girard D, et al. Interleukin-1 Is Overexpressed in Injured Muscles Following Spinal Cord Injury and Promotes Neurogenic Heterotopic Ossification. J Bone Miner Res. 2020;37(3):531-546. doi: 10.1002/jbmr.4482

 

  1. Barruet E, Morales BM, Cain CJ, et al. NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification. JCI Insight. 2018;3(22):e122958. doi: 10.1172/jci.insight.122958

 

  1. Salga M, Samuel SG, Tseng HW, et al. Bacterial Lipopolysaccharides Exacerbate Neurogenic Heterotopic Ossification Development. J Bone Miner Res. 2023;38(11):1700-1717. doi: 10.1002/jbmr.4905

 

  1. Li P, Gao Y, Zhao X. The Bone–Brain Axis: Novel Insights into the Bidirectional Crosstalk in Depression and Osteoporosis. Biomolecules. 2026;16(2):213. doi: 10.3390/biom16020213

 

  1. Dilawar M, Yu X, Jin Y, et al. Notch signaling pathway in osteogenesis, bone development, metabolism, and diseases. FASEB J. 2025;39(4):e70417. doi: 10.1096/fj.202402545R

 

  1. Varney S, Vernau K, Brown C, Toedebusch C, Vo J, Bannasch D. A Splice Acceptor Variant in DLL3 Is Associated with Spondylocostal Dysostosis in a Litter of Mixed-Breed Dogs. Genes. 2026;17(2):131. doi: 10.3390/genes17020131

 

  1. Hannani MT, Thudium CS, Karsdal MA, et al. From biochemical markers to molecular endotypes of osteoarthritis: a review on validated biomarkers. Expert Rev Molec Diagn. 2024;24(1-2):23-38. doi: 10.1080/14737159.2024.2315282

 

  1. Liu J, Yang J, Wu Q, et al. Review of osteokines in spinal cord injury: potential biomarkers during rehabilitation. J Orthop Surg Res. 2025;20(1):64. doi: 10.1186/s13018-024-05415-2

 

  1. Kruse C, Eiken P, Vestergaard P. Machine Learning Principles Can Improve Hip Fracture Prediction. Calcif Tissue Int. 2017;100(4):348-360. doi: 10.1007/s00223-017-0238-7

 

  1. Assefa F, Lim J, Kim JA, et al. Secretoneurin, a Neuropeptide, Enhances Bone Regeneration in a Mouse Calvarial Bone Defect Model. Tissue Eng Regen Med. 2021;18(2):315-324. doi: 10.1007/s13770-020-00304-1

 

  1. Khadir A, Kavalakatt S, Madhu D, et al. Spexin as an indicator of beneficial effects of exercise in human obesity and diabetes. Sci Rep. 2020;10(1):10635. doi: 10.1038/s41598-020-67624-z

 

  1. Bonnet N, Gadois C, McCloskey E, et al. Protective effect of β blockers in postmenopausal women: Influence on fractures, bone density, micro and macroarchitecture. Bone. 2007;40(5):1209-1216. doi: 10.1016/j.bone.2007.01.006

 

  1. Candellier A, Issa N, Grissi M, et al. Indoxyl-sulfate activation of the AhR- NF-κB pathway promotes interleukin-6 secretion and the subsequent osteogenic differentiation of human valvular interstitial cells from the aortic valve. J Mol Cell Cardiol. 2023;179:18-29. doi: 10.1016/j.yjmcc.2023.03.011

 

  1. Xia W, Xie J, Cai Z, et al. Damaged brain accelerates bone healing by releasing small extracellular vesicles that target osteoprogenitors. Nat Commun. 2021;12(1):6043. doi: 10.1038/s41467-021-26302-y

 

  1. Chen SY, Lin M chieh, Tsai JS, et al. Exosomal 2′,3′-CNP from mesenchymal stem cells promotes hippocampus CA1 neurogenesis/neuritogenesis and contributes to rescue of cognition/learning deficiencies of damaged brain. Stem Cells Transl Med. 2020;9(4):499-517. doi: 10.1002/sctm.19-0174

 

  1. Pu P, Wu S, Zhang K, et al. Mechanical force induces macrophage-derived exosomal UCHL3 promoting bone marrow mesenchymal stem cell osteogenesis by targeting SMAD1. J Nanobiotechnol. 2023;21(1):88. doi: 10.1186/s12951-023-01836-z

 

  1. Yi W, Han X, Wang F, et al. Acousto-Electric Conversion Fiber Networks via Regional Activation of Schwann Cell- Derived Exosomes for Neurogenic Bone Regeneration. Research. 2025;8:0769. doi: 10.34133/research.0769

 

  1. Xue P, Wang S, Lyu X, et al. PGE2/EP4 skeleton interoception activity reduces vertebral endplate porosity and spinal pain with low-dose celecoxib. Bone Res. 2021;9(1):36. doi: 10.1038/s41413-021-00155-z

 

  1. Yang D, Xu J, Xu K, Xu P. Skeletal interoception in osteoarthritis. Bone Res. 2024;12(1):22. doi: 10.1038/s41413-024-00328-6

 

  1. Yang F, Liu Y, Chen S, et al. A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress– induced bone loss. J Clin Invest. 2020;130(12):6539-6554. doi: 10.1172/JCI136105

 

  1. Wu J, Li H, He J, et al. Downregulation of microRNA-9-5p promotes synaptic remodeling in the chronic phase after traumatic brain injury. Cell Death Dis. 2021;12(1):9. doi: 10.1038/s41419-020-03329-5

 

  1. Fan J, Lee CS, Kim S, Chen C, Aghaloo T, Lee M. Generation of Small RNA-Modulated Exosome Mimetics for Bone Regeneration. ACS Nano. 2020;14(9):11973-11984. doi: 10.1021/acsnano.0c05122

 

  1. Tower RJ, Li Z, Cheng YH, et al. Spatial transcriptomics reveals a role for sensory nerves in preserving cranial suture patency through modulation of BMP/TGF-β signaling. Proc Natl Acad Sci USA. 2021;118(42):e2103087118. doi: 10.1073/pnas.2103087118

 

  1. Pei F, Ma L, Guo T, et al. Sensory nerve regulates progenitor cells via FGF-SHH axis in tooth root morphogenesis. Development. 2024;151(2):dev202043. doi: 10.1242/dev.202043

 

  1. Sahbani K, Nyman JS, Button M, Hadjiargyrou M, Bauman WA, Tawfeek HA. Attenuation of Transforming Growth Factor‐β Signaling Promotes Complete Recovery of Trabecular Bone Structure Following Immobilization With Traumatic Spinal Cord Injury. FASEB J. 2026;40(4):e71531. doi: 10.1096/fj.202504448R

 

  1. Fowler TW, Acevedo C, Mazur CM, et al. Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis. Sci Rep. 2017;7(1):44618. doi: 10.1038/srep44618

 

  1. Azhideh A, Chansky H, Yousefiasl M, et al. Recurrence of neurogenic heterotopic ossification after surgical excision and preventive strategies: A systematic review and meta-analysis. J Spinal Cord Med. 2025:1-13. doi: 10.1080/10790268.2025.2571821

 

  1. Zhu S, Zhu J, Zhen G, et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J Clin Invest. 2019;129(3):1076-1093. doi: 10.1172/JCI121561

 

  1. Hu J, Huang H, Xi Z, et al. LncRNA SEMA3B-AS1 inhibits breast cancer progression by targeting miR-3940/KLLN axis. Cell Death Dis. 2022;13(9):800. doi: 10.1038/s41419-022-05189-7

 

  1. Zhang J, Acosta FM, Wang X, et al. Osteocyte connexin hemichannels and prostaglandin E2 release dictate bone marrow mesenchymal stromal cell commitment. Proc Natl Acad Sci USA. 2025;122(7):e2412144122. doi: 10.1073/pnas.2412144122

 

  1. Chen Y, Zhang Z, Ti H, Wu J, Yuan F lai, Li X. Sympathetic cholinergic nerve fibres promote BMSC differentiation into osteoblasts via NRTN secretion: a potential treatment for osteoporosis. J Orthop Surg Res. 2025;20(1):571. doi: 10.1186/s13018-025-05944-4

 

  1. Jin Z, Chen Z, Liang T, et al. Accelerated fracture healing accompanied with traumatic brain injury: A review of clinical studies, animal models and potential mechanisms. J Orthop Transl. 2025;50:71-84. doi: 10.1016/j.jot.2024.10.008

 

  1. Andriot T, Ghosh M, Pearse DD. Engineered Healing: Synergistic Use of Schwann Cells and Biomaterials for Spinal Cord Regeneration. Intl J Molec Sci. 2025;26(16):7922. doi: 10.3390/ijms26167922

 

  1. Alhamdi AA, Mackie S, Trueman RP, Rayner MLD. Pharmacologically targeting Schwann cells to improve regeneration following nerve damage. Front Cell Dev Biol. 2025;13:1603752. doi: 10.3389/fcell.2025.1603752

 

  1. Lee CC, Wang CY, Yen HK, et al. Zoledronate Sequential Therapy After Denosumab Discontinuation to Prevent Bone Mineral Density Reduction: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(11):e2443899. doi: 10.1001/jamanetworkopen.2024.43899

 

  1. Wang Z, Wang Y, Yan J, et al. Pharmaceutical electrospinning and 3D printing scaffold design for bone regeneration. Adv Drug Deliv Rev. 2021;174:504-534. doi: 10.1016/j.addr.2021.05.007

 

  1. Holt DW, Henderson ML, Stockdale CE, et al. Osteoarthritis-like changes in the heterozygous sedc mouse associated with the HtrA1–Ddr2–Mmp-13 degradative pathway: a new model of osteoarthritis. Osteoarthr Cartil. 2012;20(5):430- 439. doi: 10.1016/j.joca.2011.11.008

 

  1. Cardoneanu A, Macovei LA, Burlui AM, et al. Temporomandibular Joint Osteoarthritis: Pathogenic Mechanisms Involving the Cartilage and Subchondral Bone, and Potential Therapeutic Strategies for Joint Regeneration. Int J Mol Sci. 2022;24(1):171. doi: 10.3390/ijms24010171

 

  1. Tang Y, Wang Z, Cao J, Tu Y. Bone–brain crosstalk in osteoarthritis: pathophysiology and interventions. Trends Mol Med. 2025;31(3):281-295. doi: 10.1016/j.molmed.2024.09.006

 

  1. Loftus TJ, Efron PA, Moldawer LL, Mohr AM. β-Blockade use for Traumatic Injuries and Immunomodulation: A Review of Proposed Mechanisms and Clinical Evidence. Shock. 2016;46(4):341-351. doi: 10.1097/SHK.0000000000000636

 

  1. Wang X, Yu Y, Zhang R, Xu J, Kang Q. Enhanced Bone Regeneration by Schwann Cells through Coupling of Osteogenesis and Angiogenesis via β-catenin signaling in a Preclinical Model of Distraction Osteogenesis. Int J Med Sci. 2025;22(1):209-226. doi: 10.7150/ijms.100854

 

  1. Wang W, Huang D, Ren J, et al. Optogenetic control of mesenchymal cell fate towards precise bone regeneration. Theranostics. 2019;9(26):8196-8205. doi: 10.7150/thno.36455

 

  1. Gupta A, Rana M, Mondal N. Determining the optimal design parameters for gyroids using computational fluid dynamics analysis under a non-Newtonian perfusion system. Biomed Eng Adv. 2025;9:100153. doi: 10.1016/j.bea.2025.100153
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