Hallmarks of peripheral nerve function in bone regeneration

Abstract

Skeletal tissue is highly innervated. Although different types of nerves have been recently identified in the bone, the crosstalk between bone and nerves remains unclear. In this review, we outline the role of the peripheral nervous system (PNS) in bone regeneration following injury. We first introduce the conserved role of nerves in tissue regeneration in species ranging from amphibians to mammals. We then present the distribution of the PNS in the skeletal system under physiological conditions, fractures, or regeneration. Furthermore, we summarize the ways in which the PNS communicates with bone-lineage cells, the vasculature, and immune cells in the bone microenvironment. Based on this comprehensive and timely review, we conclude that the PNS regulates bone regeneration through neuropeptides or neurotransmitters and cells in the peripheral nerves. An in-depth understanding of the roles of peripheral nerves in bone regeneration will inform the development of new strategies based on bone-nerve crosstalk in promoting bone repair and regeneration.

References

[1] Wang, W. et al. Changes in regeneration-responsive enhancers shape regenerative capacities in vertebrates. Science 369 (2020).

[2] Poss KD. Advances in understanding tissue regenerative capacity and mechanisms in animals. Nat. Rev. Genet, 2010, 11: 710-722

[3] Maden M. The evolution of regeneration – where does that leave mammals? Int. J. Dev. Biol., 2018, 62: 369-372

[4] Tanaka EM. The molecular and cellular choreography of appendage regeneration. Cell, 2016, 165: 1598-1608

[5] Kaucká M, Adameyko I. Non-canonical functions of the peripheral nerve. Exp. Cell Res., 2014, 321: 17-24

[6] Jarret A et al. Enteric nervous system-derived IL-18 orchestrates mucosal barrier immunity. Cell, 2020, 180: 50-63.e12

[7] Wang H, Foong JPP, Harris NL, Bornstein JC. Enteric neuroimmune interactions coordinate intestinal responses in health and disease. Mucosal. Immunol, 2020, 15: 27-39

[8] Jessen KR, Mirsky R, Lloyd AC. Schwann cells: development and role in nerve repair. Cold Spring Harb. Perspect. Biol., 2015, 7: a020487

[9] Yang H et al. HMGB1 released from nociceptors mediates inflammation. Proc. Natl. Acad. Sci. USA, 2021, 118: e2102034118

[10] Donegà M et al. Human-relevant near-organ neuromodulation of the immune system via the splenic nerve. Proc. Natl. Acad. Sci. USA, 2021, 118: e2025428118

[11] Liu T et al. Local sympathetic innervations modulate the lung innate immune responses. Sci. Adv., 2020, 6: eaay1497

[12] Gabanyi I et al. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell, 2016, 164: 378-391

[13] Tomlinson RE et al. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Rep., 2016, 16: 2723-2735

[14] Chang H-M, Wu H-C, Sun Z-G, Lian F, Leung PCK. Neurotrophins and glial cell line-derived neurotrophic factor in the ovary: physiological and pathophysiological implications. Hum. Reprod. Update, 2019, 25: 224-242

[15] Matsuda H et al. Role of nerve growth factor in cutaneous wound healing: accelerating effects in normal and healing-impaired diabetic mice. J. Exp. Med., 1998, 187: 297-306

[16] Meloni M et al. Nerve growth factor promotes cardiac repair following myocardial infarction. Circ. Res., 2010, 106: 1275-1284

[17] Rinkevich Y et al. Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration. Proc. Natl. Acad. Sci. USA, 2014, 111: 9846-9851

[18] Lee S et al. NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma. Nat. Commun., 2021, 12

[19] Todd TJ. On the process of reproduction of the members of the aquatic salamander. Q. J. Sci. Lit. Arts, 1823, 16: 84-96

[20] Joven A, Elewa A, Simon A. Model systems for regeneration: salamanders. Development, 2019, 146: dev167700

[21] Boilly B, Faulkner S, Jobling P, Hondermarck H. Nerve dependence: from regeneration to cancer. Cancer Cell, 2017, 31: 342-354

[22] Kumar A, Brockes JP. Nerve dependence in tissue, organ, and appendage regeneration. Trends Neurosci., 2012, 35: 691-699

[23] Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat. Rev. Rheumatol., 2015, 11: 45-54

[24] Song D et al. Denervation impairs bone regeneration during distraction osteogenesis in rabbit tibia lengthening. Acta Orthop., 2012, 83: 406-410

[25] Jones RE et al. Skeletal stem cell-schwann cell circuitry in mandibular repair. Cell Rep, 2019, 28: 2757-2766.e5

[26] Stocum DL. The role of peripheral nerves in urodele limb regeneration. Eur. J. Neurosci., 2011, 34: 908-916

[27] Singer M, Egloff FRL. The nervous system and regeneration of the forelimb of adult Triturus; the effect of limited nerve quantities on regeneration. J. Exp. Zool., 1949, 111: 295-314

[28] Endo T, Bryant SV, Gardiner DM. A stepwise model system for limb regeneration. Dev. Biol., 2004, 270: 135-145

[29] Tomlinson BL, Globus M, Vethamany-Globus S. Promotion of mitosis in cultured newt limb regenerates by a diffusible nerve factor. Vitro, 1981, 17: 167-172

[30] Smith MJ, Globus M, Vethamany-Globus S. Nerve extracts and substance P activate the phosphatidylinositol signaling pathway and mitogenesis in newt forelimb regenerates. Dev. Biol., 1995, 167: 239-251

[31] Globus M, Smith MJ, Vethamany-Globus S. Evidence supporting a mitogenic role for substance P in amphibian limb regeneration. Involvement of the inositol phospholipid signaling pathway. Ann. N. Y. Acad. Sci., 1991, 632: 396-399

[32] Currie JD et al. Live imaging of axolotl digit regeneration reveals spatiotemporal choreography of diverse connective tissue progenitor pools. Dev. Cell, 2016, 39: 411-423

[33] Makanae A, Mitogawa K, Satoh A. Co-operative Bmp- and Fgf-signaling inputs convert skin wound healing to limb formation in urodele amphibians. Dev. Biol., 2014, 396: 57-66

[34] Satoh A, Makanae A, Nishimoto Y, Mitogawa K. FGF and BMP derived from dorsal root ganglia regulate blastema induction in limb regeneration in Ambystoma mexicanum. Dev. Biol., 2016, 417: 114-125

[35] Brockes JP, Kintner CR. Glial growth factor and nerve-dependent proliferation in the regeneration blastema of Urodele amphibians. Cell, 1986, 45: 301-306

[36] Kumar A, Godwin JW, Gates PB, Garza-Garcia AA, Brockes JP. Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science, 2007, 318: 772-777

[37] Mescher AL, Connell E, Hsu C, Patel C, Overton B. Transferrin is necessary and sufficient for the neural effect on growth in amphibian limb regeneration blastemas. Dev. Growth Differ., 1997, 39: 677-684

[38] Wang L, Marchionni MA, Tassava RA. Cloning and neuronal expression of a type III newt neuregulin and rescue of denervated, nerve-dependent newt limb blastemas by rhGGF2. J. Neurobiol., 2000, 43: 150-158

[39] Farkas JE, Freitas PD, Bryant DM, Whited JL, Monaghan JR. Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration. Development, 2016, 143: 2724-2731

[40] Rosenberg AF, Wolman MA, Franzini-Armstrong C, Granato M. In vivo nerve-macrophage interactions following peripheral nerve injury. J. Neurosci., 2012, 32: 3898-3909

[41] Havrilak JA, Al-Shaer L, Baban N, Akinci N, Layden MJ. Characterization of the dynamics and variability of neuronal subtype responses during growth, degrowth, and regeneration of Nematostella vectensis. BMC Biol., 2021, 19

[42] Sugiyama T, Wanek N. Genetic analysis of developmental mechanisms in hydra. XXI. Enhancement of regeneration in a regeneration-deficient mutant strain by the elimination of the interstitial cell lineage. Dev. Biol., 1993, 160: 64-72

[43] Yazawa S, Umesono Y, Hayashi T, Tarui H, Agata K. Planarian Hedgehog/Patched establishes anterior-posterior polarity by regulating Wnt signaling. Proc. Natl. Acad. Sci. USA, 2009, 106: 22329-22334

[44] Huet M. [Role of the nervous system during the regeneration of an arm in a starfish: Asterina gibbosa Penn. (Echinodermata, Asteriidae)]. J. Embryol. Exp. Morphol., 1975, 33: 535-552

[45] Sehring IM, Jahn C, Weidinger G. Zebrafish fin and heart: what’s special about regeneration? Curr. Opin. Genet Dev., 2016, 40: 48-56

[46] Buckley, G., Wong, J., Metcalfe, A. D. & Ferguson, M. W. J. Denervation affects regenerative responses in MRL/MpJ and repair in C57BL/6 ear wounds. J. Anat. 220, 3–12 (2012).

[47] Johnston APW et al. Dedifferentiated Schwann cell precursors secreting paracrine factors are required for regeneration of the mammalian digit tip. Cell Stem Cell, 2016, 19: 433-448

[48] Stocum DL. Mechanisms of urodele limb regeneration. Regeneration (Oxf.), 2017, 4: 159-200

[49] Grassme KS et al. Mechanism of action of secreted newt anterior gradient protein. PLoS One, 2016, 11: e0154176

[50] Hay ED, Fischman DA. Origin of the blastema in regenerating limbs of the newt Triturus viridescens. An autoradiographic study using tritiated thymidine to follow cell proliferation and migration. Dev. Biol., 1961, 3: 26-59

[51] Lehoczky JA, Robert B, Tabin CJ. Mouse digit tip regeneration is mediated by fate-restricted progenitor cells. Proc. Natl. Acad. Sci. USA, 2011, 108: 20609-20614

[52] Rinkevich Y, Lindau P, Ueno H, Longaker MT, Weissman IL. Germ-layer and lineage-restricted stem/progenitors regenerate the mouse digit tip. Nature, 2011, 476: 409-413

[53] Stewart S, Stankunas K. Limited dedifferentiation provides replacement tissue during zebrafish fin regeneration. Dev. Biol., 2012, 365: 339-349

[54] Storer, M. A. et al. Acquisition of a unique mesenchymal precursor-like blastema state underlies successful adult mammalian digit tip regeneration. Dev. Cell 52, 509–524.e9 (2020).

[55] Carr, M. J. et al. Mesenchymal precursor cells in adult nerves contribute to mammalian tissue repair and regeneration. Cell Stem Cell 24, 240–256.e9 (2019).

[56] Pirotte N, Leynen N, Artois T, Smeets K. Do you have the nerves to regenerate? The importance of neural signalling in the regeneration process. Dev. Biol., 2016, 409: 4-15

[57] Hunt SP, Mantyh PW. The molecular dynamics of pain control. Nat. Rev. Neurosci., 2001, 2: 83-91

[58] Abraira VE, Ginty DD. The sensory neurons of touch. Neuron, 2013, 79: 618-639

[59] Jimenez-Andrade JM et al. Capsaicin-sensitive sensory nerve fibers contribute to the generation and maintenance of skeletal fracture pain. Neuroscience, 2009, 162: 1244-1254

[60] Ivanusic JJ, Mahns DA, Sahai V, Rowe MJ. Absence of large-diameter sensory fibres in a nerve to the cat humerus. J. Anat., 2006, 208: 251-255

[61] Castañeda-Corral G et al. The majority of myelinated and unmyelinated sensory nerve fibers that innervate bone express the tropomyosin receptor kinase A. Neuroscience, 2011, 178: 196-207

[62] Nencini S, Ivanusic J. Mechanically sensitive Aδ nociceptors that innervate bone marrow respond to changes in intra-osseous pressure. J. Physiol., 2017, 595: 4399-4415

[63] Dale Purves, G. J. A., Fitzpatrick, D., Hall, W. C., LaMantia, A.-S. & White, L. E. Neuroscience. 5th edn (Sinauer Associates, 2012).

[64] Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharm. Rev., 2004, 56: 331-349

[65] Espay AJ, LeWitt PA, Kaufmann H. Norepinephrine deficiency in Parkinson’s disease: the case for noradrenergic enhancement. Mov. Disord., 2014, 29: 1710-1719

[66] Ekblad E et al. Neuropeptide Y co-exists and co-operates with noradrenaline in perivascular nerve fibers. Regul. Pept., 1984, 8: 225-235

[67] Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron, 2012, 76: 116-129

[68] Hoover, D. B. Cholinergic modulation of the immune system presents new approaches for treating inflammation. Pharmacol. Ther. 179, 1–16 (2017).

[69] Mashaghi A et al. Neuropeptide substance P and the immune response. Cell Mol. Life Sci., 2016, 73: 4249-4264

[70] Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev., 2014, 94: 1099-1142

[71] Hill EL, Elde R. Distribution of CGRP-, VIP-, D beta H-, SP-, and NPY-immunoreactive nerves in the periosteum of the rat. Cell Tissue Res., 1991, 264: 469-480

[72] Bjurholm A, Kreicbergs A, Brodin E, Schultzberg M. Substance P- and CGRP-immunoreactive nerves in bone. Peptides, 1988, 9: 165-171

[73] Woolf CJ, Ma Q. Nociceptors-noxious stimulus detectors. Neuron, 2007, 55: 353-364

[74] Zhong J, Pevny L, Snider WD. “Runx“ing towards sensory differentiation. Neuron, 2006, 49: 325-327

[75] Lallemend F, Ernfors P. Molecular interactions underlying the specification of sensory neurons. Trends Neurosci., 2012, 35: 373-381

[76] Lorenz MR, Brazill JM, Beeve AT, Shen I, Scheller EL. A Neuroskeletal Atlas: spatial mapping and contextualization of axon subtypes innervating the long bones of C3H and B6 mice. J. Bone Min. Res., 2021, 36: 1012-1025

[77] Mach DB et al. Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience, 2002, 113: 155-166

[78] Matsuo K et al. Innervation of the tibial epiphysis through the intercondylar foramen. Bone, 2019, 120: 297-304

[79] Anderson CR, Bergner A, Murphy SM. How many types of cholinergic sympathetic neuron are there in the rat stellate ganglion? Neuroscience, 2006, 140: 567-576

[80] Asmus, S. E., Tian, H. & Landis, S. C. Induction of cholinergic function in cultured sympathetic neurons by periosteal cells: cellular mechanisms. Dev. Biol. 235, 1–11 (2001).

[81] Bajayo A et al. Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual. Proc. Natl. Acad. Sci. USA, 2012, 109: 15455-15460

[82] Salhotra A, Shah HN, Levi B, Longaker MT. Mechanisms of bone development and repair. Nat. Rev. Mol. Cell Biol., 2020, 21: 696-711

[83] Xing W, Cheng S, Wergedal J, Mohan S. Epiphyseal chondrocyte secondary ossification centers require thyroid hormone activation of Indian hedgehog and osterix signaling. J. Bone Min. Res., 2014, 29: 2262-2275

[84] Sisask G, Silfverswärd CJ, Bjurholm A, Nilsson O. Ontogeny of sensory and autonomic nerves in the developing mouse skeleton. Auton. Neurosci., 2013, 177: 237-243

[85] Sudiwala S, Knox SM. The emerging role of cranial nerves in shaping craniofacial development. Genesis, 2019, 57: e23282

[86] Ramaesh T, Bard JBL. The growth and morphogenesis of the early mouse mandible: a quantitative analysis. J. Anat., 2003, 203: 213-222

[87] Tower, R. J. 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 118, e2103087118 (2021).

[88] Carmeliet P, Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. Nature, 2005, 436: 193-200

[89] Wehrwein EA, Orer HS, Barman SM. Overview of the anatomy, physiology, and pharmacology of the autonomic nervous system. Compr. Physiol., 2016, 6: 1239-1278

[90] Evans SF, Chang H, Knothe Tate ML. Elucidating multiscale periosteal mechanobiology: a key to unlocking the smart properties and regenerative capacity of the periosteum? Tissue Eng. Part B Rev., 2013, 19: 147-159

[91] Clarke B. Normal bone anatomy and physiology. Clin. J. Am. Soc. Nephrol., 2008, 3: S131-S139

[92] Chartier SR, Mitchell SAT, Majuta LA, Mantyh PW. The changing sensory and sympathetic innervation of the young, adult and aging mouse femur. Neuroscience, 2018, 387: 178-190

[93] Pazzaglia UE, Congiu T, Raspanti M, Ranchetti F, Quacci D. Anatomy of the intracortical canal system: scanning electron microscopy study in rabbit femur. Clin. Orthop. Relat. Res., 2009, 467: 2446-2456

[94] Marrella A et al. Engineering vascularized and innervated bone biomaterials for improved skeletal tissue regeneration. Mater. Today (Kidlington), 2018, 21: 362-376

[95] Grönblad M, Liesi P, Korkala O, Karaharju E, Polak J. Innervation of human bone periosteum by peptidergic nerves. Anat. Rec., 1984, 209: 297-299

[96] Ralston HJ, Miller MR, Kasahara M. Nerve endings in human fasciae, tendons, ligaments, periosteum, and joint synovial membrane. Anat. Rec., 1960, 136: 137-147

[97] Steverink JG et al. Sensory innervation of human bone: an immunohistochemical study to further understand bone pain. J. Pain., 2021, 22: 1385-1395

[98] Martin CD, Jimenez-Andrade JM, Ghilardi JR, Mantyh PW. Organization of a unique net-like meshwork of CGRP+ sensory fibers in the mouse periosteum: implications for the generation and maintenance of bone fracture pain. Neurosci. Lett., 2007, 427: 148-152

[99] Liu K, Tedeschi A, Park KK, He Z. Neuronal intrinsic mechanisms of axon regeneration. Annu. Rev. Neurosci., 2011, 34: 131-152

[100] Burnett MG, Zager EL. Pathophysiology of peripheral nerve injury: a brief review. Neurosurg. Focus, 2004, 16: E1

[101] Shin JE, Ha H, Kim YK, Cho Y, DiAntonio A. DLK regulates a distinctive transcriptional regeneration program after peripheral nerve injury. Neurobiol. Dis., 2019, 127: 178-192

[102] Shin JE, Ha H, Cho EH, Kim YK, Cho Y. Comparative analysis of the transcriptome of injured nerve segments reveals spatiotemporal responses to neural damage in mice. J. Comp. Neurol., 2018, 526: 1195-1208

[103] Villar MJ et al. Further studies on galanin-, substance P-, and CGRP-like immunoreactivities in primary sensory neurons and spinal cord: effects of dorsal rhizotomies and sciatic nerve lesions. Exp. Neurol., 1991, 112: 29-39

[104] Noguchi K, Senba E, Morita Y, Sato M, Tohyama M. Alpha-CGRP and beta-CGRP mRNAs are differentially regulated in the rat spinal cord and dorsal root ganglion. Brain Res. Mol. Brain Res., 1990, 7: 299-304

[105] Hökfelt T, Zhang X, Wiesenfeld-Hallin Z. Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci., 1994, 17: 22-30

[106] Li X-Q, Verge VMK, Johnston JM, Zochodne DW. CGRP peptide and regenerating sensory axons. J. Neuropathol. Exp. Neurol., 2004, 63: 1092-1103

[107] Zhang Y et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nat. Med., 2016, 22: 1160-1169

[108] Li J et al. Occurrence of substance P in bone repair under different load comparison of straight and angulated fracture in rat tibia. J. Orthop. Res., 2010, 28: 1643-1650

[109] Pinho-Ribeiro, F. A., Verri, W. A. & Chiu, I. M. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol. 38, 5–19 (2017).

[110] Terenzio M et al. Locally translated mTOR controls axonal local translation in nerve injury. Science, 2018, 359: 1416-1421

[111] Scheib J, Höke A. Advances in peripheral nerve regeneration. Nat. Rev. Neurol., 2013, 9: 668-676

[112] Rigoni M, Negro S. Signals orchestrating peripheral nerve repair. Cells, 2020, 9: 1768

[113] Chen P, Piao X, Bonaldo P. Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury. Acta Neuropathol., 2015, 130: 605-618

[114] Dubový P. Wallerian degeneration and peripheral nerve conditions for both axonal regeneration and neuropathic pain induction. Ann. Anat., 2011, 193: 267-275

[115] Ivanusic JJ, Sahai V, Mahns DA. The cortical representation of sensory inputs arising from bone. Brain Res., 2009, 1269: 47-53

[116] Blackwell KA, Raisz LG, Pilbeam CC. Prostaglandins in bone: bad cop, good cop? Trends Endocrinol. Metab., 2010, 21: 294-301

[117] Nencini S, Ringuet M, Kim D-H, Greenhill C, Ivanusic JJ. GDNF, neurturin, and artemin activate and sensitize bone afferent neurons and contribute to inflammatory bone pain. J. Neurosci., 2018, 38: 4899-4911

[118] Ghilardi JR et al. Sustained blockade of neurotrophin receptors TrkA, TrkB and TrkC reduces non-malignant skeletal pain but not the maintenance of sensory and sympathetic nerve fibers. Bone, 2011, 48: 389-398

[119] McMahon SB, La Russa F, Bennett DLH. Crosstalk between the nociceptive and immune systems in host defence and disease. Nat. Rev. Neurosci., 2015, 16: 389-402

[120] Schiller M, Ben-Shaanan TL, Rolls A. Neuronal regulation of immunity: why, how and where? Nat. Rev. Immunol., 2021, 21: 20-36

[121] Baral P, Udit S, Chiu IM. Pain and immunity: implications for host defence. Nat. Rev. Immunol., 2019, 19: 433-447

[122] Gudes S et al. The role of slow and persistent TTX-resistant sodium currents in acute tumor necrosis factor-α-mediated increase in nociceptors excitability. J. Neurophysiol., 2015, 113: 601-619

[123] Li Z et al. Fracture repair requires TrkA signaling by skeletal sensory nerves. J. Clin. Invest., 2019, 129: 5137-5150

[124] Skene JH. Axonal growth-associated proteins. Annu. Rev. Neurosci., 1989, 12: 127-156

[125] Feng G et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron, 2000, 28: 41-51

[126] Filipowska J, Tomaszewski KA, Niedźwiedzki Ł, Walocha JA, Niedźwiedzki T. The role of vasculature in bone development, regeneration and proper systemic functioning. Angiogenesis, 2017, 20: 291-302

[127] Li J, Ahmad T, Spetea M, Ahmed M, Kreicbergs A. Bone reinnervation after fracture: a study in the rat. J. Bone Min. Res., 2001, 16: 1505-1510

[128] Chartier SR et al. Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain. Pain, 2014, 155: 2323-2336

[129] Yasui M et al. Nerve growth factor and associated nerve sprouting contribute to local mechanical hyperalgesia in a rat model of bone injury. Eur. J. Pain, 2012, 16: 953-965

[130] Singer M. The influence of the nerve in regeneration of the amphibian extremity. Q Rev. Biol., 1952, 27: 169-200

[131] Li J, Kreicbergs A, Bergström J, Stark A, Ahmed M. Site-specific CGRP innervation coincides with bone formation during fracture healing and modeling: a study in rat angulated tibia. J. Orthop. Res., 2007, 25: 1204-1212

[132] Meyers CA et al. A neurotrophic mechanism directs sensory nerve transit in cranial bone. Cell Rep., 2020, 31: 107696

[133] Mantyh PW. The neurobiology of skeletal pain. Eur. J. Neurosci., 2014, 39: 508-519

[134] Indo, Y. NGF-dependent neurons and neurobiology of emotions and feelings: Lessons from congenital insensitivity to pain with anhidrosis. Neurosci. Biobehav. Rev. 87, 1–16 (2018).

[135] Niedermair T et al. Absence of substance P and the sympathetic nervous system impact on bone structure and chondrocyte differentiation in an adult model of endochondral ossification. Matrix Biol., 2014, 38: 22-35

[136] Landes EK, Konda SR, Davidovitch R, Egol KA. Can we predict the need for unplanned reoperation after nonunion repair. J. Orthop. Trauma, 2021, 35: 654-659

[137] Toscano E et al. Multisystem involvement in congenital insensitivity to pain with anhidrosis (CIPA), a nerve growth factor receptor(Trk A)-related disorder. Neuropediatrics, 2000, 31: 39-41

[138] Nordström D et al. Symptomatic lumbar spondylolysis. Neuroimmunologic studies. Spine (Philos. Pa 1976), 1994, 19: 2752-2758

[139] Wang X-D et al. The neural system regulates bone homeostasis via mesenchymal stem cells: a translational approach. Theranostics, 2020, 10: 4839-4850

[140] Wang L et al. Preventing early-stage graft bone resorption by simultaneous innervation: innervated iliac bone flap for mandibular reconstruction. Plast. Reconstr. Surg., 2017, 139: 1152e-1161e

[141] Bjurholm A. Neuroendocrine peptides in bone. Int. Orthop., 1991, 15: 325-329

[142] Serre CM, Farlay D, Delmas PD, Chenu C. Evidence for a dense and intimate innervation of the bone tissue, including glutamate-containing fibers. Bone, 1999, 25: 623-629

[143] Dénes A et al. Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience, 2005, 134: 947-963

[144] Takeda S et al. Leptin regulates bone formation via the sympathetic nervous system. Cell, 2002, 111: 305-317

[145] Steenbergh, P. H. et al. Structure and expression of the human calcitonin/CGRP genes. FEBS Lett. 209, 97–103 (1986).

[146] Xu J et al. The effects of calcitonin gene-related peptide on bone homeostasis and regeneration. Curr. Osteoporos. Rep., 2020, 18: 621-632

[147] Brain SD, Grant AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol. Rev., 2004, 84: 903-934

[148] Appelt J et al. The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing. EBioMedicine, 2020, 59: 102970

[149] Jia S et al. Calcitonin gene-related peptide enhances osteogenic differentiation and recruitment of bone marrow mesenchymal stem cells in rats. Exp. Ther. Med., 2019, 18: 1039-1046

[150] Zhou R, Yuan Z, Liu J, Liu J. Calcitonin gene-related peptide promotes the expression of osteoblastic genes and activates the WNT signal transduction pathway in bone marrow stromal stem cells. Mol. Med. Rep., 2016, 13: 4689-4696

[151] Mrak E et al. Calcitonin gene-related peptide (CGRP) inhibits apoptosis in human osteoblasts by β-catenin stabilization. J. Cell Physiol., 2010, 225: 701-708

[152] Zhang Q et al. Receptor activity-modifying protein 1 regulates the phenotypic expression of BMSCs via the Hippo/Yap pathway. J. Cell Physiol., 2019, 234: 13969-13976

[153] Cao YQ et al. Primary afferent tachykinins are required to experience moderate to intense pain. Nature, 1998, 392: 390-394

[154] Villa I, Mrak E, Rubinacci A, Ravasi F, Guidobono F. CGRP inhibits osteoprotegerin production in human osteoblast-like cells via cAMP/PKA-dependent pathway. Am. J. Physiol. Cell Physiol., 2006, 291: C529-C537

[155] Mi J et al. Implantable electrical stimulation at dorsal root ganglions accelerates osteoporotic fracture healing via calcitonin gene-related peptide. Adv. Sci. (Weinh.), 2022, 9: e2103005

[156] Liu H-J et al. Substance P promotes the proliferation, but inhibits differentiation and mineralization of osteoblasts from rats with spinal cord injury via RANKL/OPG system. PLoS One, 2016, 11: e0165063

[157] Goto T et al. Substance P stimulates late-stage rat osteoblastic bone formation through neurokinin-1 receptors. Neuropeptides, 2007, 41: 25-31

[158] Wang L et al. Substance P stimulates bone marrow stromal cell osteogenic activity, osteoclast differentiation, and resorption activity in vitro. Bone, 2009, 45: 309-320

[159] Aoki M, Tamai K, Saotome K. Substance P- and calcitonin gene-related peptide-immunofluorescent nerves in the repair of experimental bone defects. Int. Orthop., 1994, 18: 317-324

[160] Zou Z et al. Correlation of neuropeptides substance P and neuropeptide Y and their receptors with fracture healing in rats. Mater. Express, 2020, 10: 240-250

[161] Fu S et al. Neuropeptide substance P improves osteoblastic and angiogenic differentiation capacity of bone marrow stem cells in vitro. Biomed. Res. Int., 2014, 2014: 596023

[162] Mei G et al. Substance P activates the Wnt signal transduction pathway and enhances the differentiation of mouse preosteoblastic MC3T3-E1 cells. Int. J. Mol. Sci., 2014, 15: 6224-6240

[163] Mu C et al. Substance P-embedded multilayer on titanium substrates promotes local osseointegration via MSC recruitment. J. Mater. Chem. B, 2020, 8: 1212-1222

[164] Hofman M et al. Effect of neurokinin-1-receptor blockage on fracture healing in rats. Sci. Rep., 2019, 9

[165] Togari A. Adrenergic regulation of bone metabolism: possible involvement of sympathetic innervation of osteoblastic and osteoclastic cells. Microsc. Res. Tech., 2002, 58: 77-84

[166] Niedermair, T., Straub, R. H., Brochhausen, C. & Grässel, S. Impact of the sensory and sympathetic nervous system on fracture healing in ovariectomized mice. Int. J. Mol. Sci. 21, 405 (2020).

[167] Fonseca TL et al. Double disruption of α2A- and α2C-adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype. J. Bone Min. Res., 2011, 26: 591-603

[168] Huang HH, Brennan TC, Muir MM, Mason RS. Functional alpha1- and beta2-adrenergic receptors in human osteoblasts. J. Cell Physiol., 2009, 220: 267-275

[169] Tanaka K et al. α1B -Adrenoceptor signalling regulates bone formation through the up-regulation of CCAAT/enhancer-binding protein δ expression in osteoblasts. Br. J. Pharm., 2016, 173: 1058-1069

[170] Kajimura D et al. Genetic determination of the cellular basis of the sympathetic regulation of bone mass accrual. J. Exp. Med., 2011, 208: 841-851

[171] Chen H et al. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat. Commun., 2019, 10

[172] Hedderich, J. et al. Norepinephrine inhibits the proliferation of bone marrow-derived mesenchymal stem cells via β2-adrenoceptor-mediated ERK1/2 and PKA phosphorylation. Int. J. Mol. Sci. 21, 3924 (2020).

[173] Elefteriou F et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature, 2005, 434: 514-520

[174] Liang H et al. Selective β2-adrenoreceptor signaling regulates osteoclastogenesis via modulating RANKL production and neuropeptides expression in osteocytic MLO-Y4 cells. J. Cell. Biochem., 2019, 120: 7238-7247

[175] Al-Subaie AE et al. Propranolol enhances bone healing and implant osseointegration in rats tibiae. J. Clin. Periodontol., 2016, 43: 1160-1170

[176] Haffner-Luntzer M et al. Chronic psychosocial stress compromises the immune response and endochondral ossification during bone fracture healing via β-AR signaling. Proc. Natl. Acad. Sci. USA, 2019, 116: 8615-8622

[177] Khosla S et al. Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism. J. Clin. Invest., 2018, 128: 4832-4842

[178] Han, J. et al. DNA synthesis of rat bone marrow mesenchymal stem cells through alpha1-adrenergic receptors. Arch. Biochem. Biophys. 490, 96–102 (2009).

[179] Grässel SG. The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology. Arthritis Res. Ther., 2014, 16: 485

[180] Golan, K., Kollet, O., Markus, R. P. & Lapidot, T. Daily light and darkness onset and circadian rhythms metabolically synchronize hematopoietic stem cell differentiation and maintenance: the role of bone marrow norepinephrine, tumor necrosis factor, and melatonin cycles. Exp. Hematol. 78, 1–10 (2019).

[181] Sato T et al. Functional role of acetylcholine and the expression of cholinergic receptors and components in osteoblasts. FEBS Lett., 2010, 584: 817-824

[182] Liu P-S, Chen Y-Y, Feng C-K, Lin Y-H, Yu T-C. Muscarinic acetylcholine receptors present in human osteoblast and bone tissue. Eur. J. Pharm., 2011, 650: 34-40

[183] Hu H et al. Prenatal nicotine exposure retards osteoclastogenesis and endochondral ossification in fetal long bones in rats. Toxicol. Lett., 2018, 295: 249-255

[184] Negishi-Koga T, Takayanagi H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol. Rev., 2009, 231: 241-256

[185] Mandl P et al. Nicotinic acetylcholine receptors modulate osteoclastogenesis. Arthritis Res. Ther., 2016, 18: 63

[186] Al-Hamed, F. S. et al. Postoperative administration of the acetylcholinesterase inhibitor, donepezil, interferes with bone healing and implant osseointegration in a rat model. Biomolecules 10, 1318 (2020).

[187] Eimar H et al. Acetylcholinesterase inhibitors and healing of hip fracture in Alzheimer’s disease patients: a retrospective cohort study. J. Musculoskelet. Neuronal Interact., 2013, 13: 454-463

[188] Shi Y et al. Signaling through the M(3) muscarinic receptor favors bone mass accrual by decreasing sympathetic activity. Cell Metab., 2010, 11: 231-238

[189] Allison SJ, Baldock PA, Herzog H. The control of bone remodeling by neuropeptide Y receptors. Peptides, 2007, 28: 320-325

[190] Igwe JC et al. Neuropeptide Y is expressed by osteocytes and can inhibit osteoblastic activity. J. Cell. Biochem., 2009, 108: 621-630

[191] Yu W et al. Inhibition of Y1 receptor promotes osteogenesis in bone marrow stromal cells cAMP/PKA/CREB pathway. Front. Endocrinol. (Lausanne), 2020, 11: 583105

[192] Lee NJ et al. Critical role for Y1 receptors in mesenchymal progenitor cell differentiation and osteoblast activity. J. Bone Min. Res., 2010, 25: 1736-1747

[193] Liu S et al. [Neuropeptide Y Y1 receptor antagonist PD160170 promotes osteogenic differentiation of rat bone marrow mesenchymal stem cells in vitro and femoral defect repair in rats]. Nan Fang. Yi Ke Da Xue Xue Bao, 2018, 38: 669-676

[194] Zhang Y et al. Neuronal induction of bone-fat imbalance through osteocyte neuropeptide Y. Adv. Sci. (Weinh.), 2021, 8: e2100808

[195] Udit S, Blake K, Chiu IM. Somatosensory and autonomic neuronal regulation of the immune response. Nat. Rev. Neurosci., 2022, 23: 157-171

[196] Henning RJ, Sawmiller DR. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc. Res., 2001, 49: 27-37

[197] Shi L et al. Vasoactive intestinal peptide stimulates bone marrow-mesenchymal stem cells osteogenesis differentiation by activating Wnt/β-catenin signaling pathway and promotes rat skull defect repair. Stem Cells Dev., 2020, 29: 655-666

[198] Rameshwar P et al. Vasoactive intestinal peptide (VIP) inhibits the proliferation of bone marrow progenitors through the VPAC1 receptor. Exp. Hematol., 2002, 30: 1001-1009

[199] Shi L et al. Vasoactive intestinal peptide promotes fracture healing in sympathectomized mice. Calcif. Tissue Int., 2021, 109: 55-65

[200] Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharm. Ther., 2013, 138: 155-175

[201] Park, H. & Poo, M.-M. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 14, 7–23 (2013).

[202] Asaumi K, Nakanishi T, Asahara H, Inoue H, Takigawa M. Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone, 2000, 26: 625-633

[203] Kilian O et al. BDNF and its TrkB receptor in human fracture healing. Ann. Anat., 2014, 196: 286-295

[204] Xian CJ, Zhou X-F. Treating skeletal pain: limitations of conventional anti-inflammatory drugs, and anti-neurotrophic factor as a possible alternative. Nat. Clin. Pr. Rheumatol., 2009, 5: 92-98

[205] Zha K et al. Nerve growth factor (NGF) and NGF receptors in mesenchymal stem/stromal cells: impact on potential therapies. Stem Cells Transl. Med., 2021, 10: 1008-1020

[206] Su Y-W et al. Neurotrophin-3 induces BMP-2 and VEGF activities and promotes the bony repair of injured growth plate cartilage and bone in rats. J. Bone Min. Res., 2016, 31: 1258-1274

[207] Yada M, Yamaguchi K, Tsuji T. NGF stimulates differentiation of osteoblastic MC3T3-E1 cells. Biochem. Biophys. Res. Commun., 1994, 205: 1187-1193

[208] Mogi M, Kondo A, Kinpara K, Togari A. Anti-apoptotic action of nerve growth factor in mouse osteoblastic cell line. Life Sci., 2000, 67: 1197-1206

[209] Yang S et al. Effects of exogenous nerve growth factor on the expression of BMP-9 and VEGF in the healing of rabbit mandible fracture with local nerve injury. J. Orthop. Surg. Res., 2021, 16: 74

[210] Rivera KO et al. Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion. Sci. Rep., 2020, 10

[211] Koewler NJ et al. Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur. J. Bone Min. Res., 2007, 22: 1732-1742

[212] Rapp AE et al. Analgesia via blockade of NGF/TrkA signaling does not influence fracture healing in mice. J. Orthop. Res., 2015, 33: 1235-1241

[213] Yang B, Ma T-Y, Ma W. [New research of nerve growth factor on fracture healing]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao, 2020, 42: 546-551

[214] Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Annu Rev. Neurosci., 2006, 29: 507-538

[215] Liu Q, Lei L, Yu T, Jiang T, Kang Y. Effect of brain-derived neurotrophic factor on the neurogenesis and osteogenesis in bone engineering. Tissue Eng. Part A, 2018, 24: 1283-1292

[216] Zhang Z, Hu P, Wang Z, Qiu X, Chen Y. BDNF promoted osteoblast migration and fracture healing by up-regulating integrin β1 via TrkB-mediated ERK1/2 and AKT signalling. J. Cell Mol. Med., 2020, 24: 10792-10802

[217] Ai L-S et al. Inhibition of BDNF in multiple myeloma blocks osteoclastogenesis via down-regulated stroma-derived RANKL expression both in vitro and in vivo. PLoS One, 2012, 7: e46287

[218] Li X, Sun DC, Li Y, Wu XY. Neurotrophin-3 improves fracture healing in rats. Eur. Rev. Med. Pharm. Sci., 2018, 22: 2439-2446

[219] Mizuno N et al. Effect of neurotrophins on differentiation, calcification and proliferation in cultures of human pulp cells. Cell Biol. Int., 2007, 31: 1462-1469

[220] Mizuno N et al. Effect of neurotrophin-4/5 on bone/cementum-related protein expressions and DNA synthesis in cultures of human periodontal ligament cells. J. Periodontol., 2008, 79: 2182-2189

[221] Seiradake E, Jones EY, Klein R. Structural perspectives on axon guidance. Annu. Rev. Cell Dev. Biol., 2016, 32: 577-608

[222] Stoeckli, E. T. Understanding axon guidance: are we nearly there yet? Development 145, dev151415 (2018).

[223] Fukuda T et al. Sema3A regulates bone-mass accrual through sensory innervations. Nature, 2013, 497: 490-493

[224] Hayashi M et al. Osteoprotection by semaphorin 3A. Nature, 2012, 485: 69-74

[225] Kenan S et al. Investigation of the effects of semaphorin 3A on new bone formation in a rat calvarial defect model. J. Craniomaxillofac Surg., 2019, 47: 473-483

[226] Li Y, Yang L, He S, Hu J. The effect of semaphorin 3A on fracture healing in osteoporotic rats. J. Orthop. Sci., 2015, 20: 1114-1121

[227] Hughes A, Kleine-Albers J, Helfrich MH, Ralston SH, Rogers MJ. A class III semaphorin (Sema3e) inhibits mouse osteoblast migration and decreases osteoclast formation in vitro. Calcif. Tissue Int., 2012, 90: 151-162

[228] Negishi-Koga T et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat. Med., 2011, 17: 1473-1480

[229] Zhang Y, Wei L, Miron RJ, Shi B, Bian Z. Bone scaffolds loaded with siRNA-Semaphorin4d for the treatment of osteoporosis related bone defects. Sci. Rep., 2016, 6

[230] Kania A, Klein R. Mechanisms of ephrin-Eph signalling in development, physiology and disease. Nat. Rev. Mol. Cell Biol., 2016, 17: 240-256

[231] Xing W, Kim J, Wergedal J, Chen S-T, Mohan S. Ephrin B1 regulates bone marrow stromal cell differentiation and bone formation by influencing TAZ transactivation via complex formation with NHERF1. Mol. Cell Biol., 2010, 30: 711-721

[232] Arthur A et al. EphB/ephrin-B interactions mediate human MSC attachment, migration and osteochondral differentiation. Bone, 2011, 48: 533-542

[233] Wang Y et al. Ephrin B2/EphB4 mediates the actions of IGF-I signaling in regulating endochondral bone formation. J. Bone Min. Res., 2014, 29: 1900-1913

[234] Allan EH et al. EphrinB2 regulation by PTH and PTHrP revealed by molecular profiling in differentiating osteoblasts. J. Bone Min. Res., 2008, 23: 1170-1181

[235] Arthur A, Paton S, Zannettino ACW, Gronthos S. Conditional knockout of ephrinB1 in osteogenic progenitors delays the process of endochondral ossification during fracture repair. Bone, 2020, 132: 115189

[236] Wang Y et al. Ablation of Ephrin B2 in Col2 expressing cells delays fracture repair. Endocrinology, 2020, 161: bqaa179

[237] Kim B-J et al. Osteoclast-secreted SLIT3 coordinates bone resorption and formation. J. Clin. Invest., 2018, 128: 1429-1441

[238] Mediero A, Ramkhelawon B, Perez-Aso M, Moore KJ, Cronstein BN. Netrin-1 is a critical autocrine/paracrine factor for osteoclast differentiation. J. Bone Min. Res., 2015, 30: 837-854

[239] Zhu S et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J. Clin. Invest., 2019, 129: 1076-1093

[240] Nakanishi M, Rosenberg DW. Multifaceted roles of PGE2 in inflammation and cancer. Semin Immunopathol., 2013, 35: 123-137

[241] Hu B et al. Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones. J. Clin. Invest., 2020, 130: 3483-3498

[242] Lisowska B, Kosson D, Domaracka K. Positives and negatives of nonsteroidal anti-inflammatory drugs in bone healing: the effects of these drugs on bone repair. Drug Des. Devel. Ther., 2018, 12: 1809-1814

[243] Che T, Dwivedi-Agnihotri H, Shukla AK, Roth BL. Biased ligands at opioid receptors: current status and future directions. Sci. Signal, 2021, 14: eaav0320

[244] Zura R et al. Epidemiology of fracture nonunion in 18 human bones. JAMA Surg., 2016, 151: e162775

[245] Buchheit T et al. Opioid exposure is associated with nonunion risk in a traumatically injured population: an inception cohort study. Injury, 2018, 49: 1266-1271

[246] Zheng C et al. COX-2/PGE2 facilitates fracture healing by activating the Wnt/β-catenin signaling pathway. Eur. Rev. Med. Pharm. Sci., 2019, 23: 9721-9728

[247] Zhang X et al. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J. Clin. Invest., 2002, 109: 1405-1415

[248] Yoshida K et al. Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation. Proc. Natl. Acad. Sci. USA, 2002, 99: 4580-4585

[249] Gao X et al. Nociceptive nerves regulate haematopoietic stem cell mobilization. Nature, 2021, 589: 591-596

[250] Zhang X et al. Schwann cells promote prevascularization and osteogenesis of tissue-engineered bone via bone marrow mesenchymal stem cell-derived endothelial cells. Stem Cell Res. Ther., 2021, 12: 382

[251] Wu Z et al. Schwann Cell-derived exosomes promote bone regeneration and repair by enhancing the biological activity of porous Ti6Al4V scaffolds. Biochem. Biophys. Res. Commun., 2020, 531: 559-565

[252] Xie M et al. Schwann cell precursors contribute to skeletal formation during embryonic development in mice and zebrafish. Proc. Natl. Acad. Sci. USA, 2019, 116: 15068-15073

[253] Kaukua N et al. Glial origin of mesenchymal stem cells in a tooth model system. Nature, 2014, 513: 551-554

[254] Chen B, Banton MC, Singh L, Parkinson DB, Dun X-P. Single cell transcriptome data analysis defines the heterogeneity of peripheral nerve cells in homeostasis and regeneration. Front. Cell Neurosci., 2021, 15: 624826

[255] Roelofs AJ, Thompson K, Gordon S, Rogers MJ. Molecular mechanisms of action of bisphosphonates: current status. Clin. Cancer Res., 2006, 12: 6222s-6230s

[256] Xie D et al. Sensory denervation increases potential of bisphosphonates to induce osteonecrosis via disproportionate expression of calcitonin gene-related peptide and substance P. Ann. N. Y. Acad. Sci., 2021, 1487: 56-73

[257] Tuzmen C, Campbell PG. Crosstalk between neuropeptides SP and CGRP in regulation of BMP2-induced bone differentiation. Connect Tissue Res., 2018, 59: 81-90

[258] Drissi H, Hott M, Marie PJ, Lasmoles F. Expression of the CT/CGRP gene and its regulation by dibutyryl cyclic adenosine monophosphate in human osteoblastic cells. J. Bone Min. Res., 1997, 12: 1805-1814

[259] Zhang R, Liang Y, Wei S. The expressions of NGF and VEGF in the fracture tissues are closely associated with accelerated clavicle fracture healing in patients with traumatic brain injury. Ther. Clin. Risk Manag., 2018, 14: 2315-2322

[260] Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell, 2011, 146: 873-887

[261] Martin P, Lewis J. Origins of the neurovascular bundle: interactions between developing nerves and blood vessels in embryonic chick skin. Int. J. Dev. Biol., 1989, 33: 379-387

[262] Mukouyama Y-S, Gerber H-P, Ferrara N, Gu C, Anderson DJ. Peripheral nerve-derived VEGF promotes arterial differentiation via neuropilin 1-mediated positive feedback. Development, 2005, 132: 941-952

[263] Li W et al. Peripheral nerve-derived CXCL12 and VEGF-A regulate the patterning of arterial vessel branching in developing limb skin. Dev. Cell, 2013, 24: 359-371

[264] Hjelmeland AB, Lathia JD, Sathornsumetee S, Rich JN. Twisted tango: brain tumor neurovascular interactions. Nat. Neurosci., 2011, 14: 1375-1381

[265] Hosoi T, Okuma Y, Matsuda T, Nomura Y. Novel pathway for LPS-induced afferent vagus nerve activation: possible role of nodose ganglion. Auton. Neurosci., 2005, 120: 104-107

[266] Xu Z-Z et al. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat. Med., 2015, 21: 1326-1331

[267] Pavlov VA, Chavan SS, Tracey KJ. Molecular and functional neuroscience in immunity. Annu. Rev. Immunol., 2018, 36: 783-812

[268] Mi, J. et al. Calcitonin gene-related peptide enhances distraction osteogenesis by increasing angiogenesis. Tissue Eng. Part A 27, 87–102 (2021).

[269] Xu R et al. Targeting skeletal endothelium to ameliorate bone loss. Nat. Med., 2018, 24: 823-833

[270] Godinho-Silva C, Cardoso F, Veiga-Fernandes H. Neuro-immune cell units: a new paradigm in physiology. Annu. Rev. Immunol., 2019, 37: 19-46

[271] Pajarinen J et al. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials, 2019, 196: 80-89

[272] Shapouri-Moghaddam A et al. Macrophage plasticity, polarization, and function in health and disease. J. Cell Physiol., 2018, 233: 6425-6440

[273] Wang L et al. Calcitonin-gene-related peptide stimulates stromal cell osteogenic differentiation and inhibits RANKL induced NF-kappaB activation, osteoclastogenesis and bone resorption. Bone, 2010, 46: 1369-1379

[274] Yuan Y et al. Deficiency of calcitonin gene-related peptide affects macrophage polarization in osseointegration. Front. Physiol., 2020, 11: 733

[275] McWhorter FY, Wang T, Nguyen P, Chung T, Liu WF. Modulation of macrophage phenotype by cell shape. Proc. Natl. Acad. Sci. USA, 2013, 110: 17253-17258

[276] Xu Y et al. Inferior alveolar nerve transection disturbs innate immune responses and bone healing after tooth extraction. Ann. N. Y. Acad. Sci., 2019, 1448: 52-64

[277] Zhang Q et al. CGRP-modulated M2 macrophages regulate osteogenesis of MC3T3-E1 via Yap1. Arch. Biochem. Biophys., 2021, 697: 108697

[278] Baral P et al. Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia. Nat. Med., 2018, 24: 417-426

[279] Clézardin P et al. Bone metastasis: mechanisms, therapies, and biomarkers. Physiol. Rev., 2021, 101: 797-855

[280] Gold DT, Solimeo S. Osteoporosis and depression: a historical perspective. Curr. Osteoporos. Rep., 2006, 4: 134-139

[281] Kelly RR, McDonald LT, Jensen NR, Sidles SJ, LaRue AC. Impacts of psychological stress on osteoporosis: clinical implications and treatment interactions. Front. Psychiatry, 2019, 10: 200

[282] Ambrosi TH et al. Aged skeletal stem cells generate an inflammatory degenerative niche. Nature, 2021, 597: 256-262

[283] Chandra A, Rajawat J. Skeletal aging and osteoporosis: mechanisms and therapeutics. Int. J. Mol. Sci., 2021, 22: 3553

[284] Ducy P et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell, 2000, 100: 197-207

[285] Strotmeyer ES et al. Reduced peripheral nerve function is related to lower hip BMD and calcaneal QUS in older white and black adults: the Health, Aging, and Body Composition Study. J. Bone Min. Res., 2006, 21: 1803-1810

[286] Farr JN et al. Relationship of sympathetic activity to bone microstructure, turnover, and plasma osteopontin levels in women. J. Clin. Endocrinol. Metab., 2012, 97: 4219-4227

[287] Tomlinson RE, Christiansen BA, Giannone AA, Genetos DC. The role of nerves in skeletal development, adaptation, and aging. Front. Endocrinol. (Lausanne), 2020, 11: 646-646

[288] Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat. Rev. Rheumatol., 2012, 8: 390-398

[289] Latourte A, Kloppenburg M, Richette P. Emerging pharmaceutical therapies for osteoarthritis. Nat. Rev. Rheumatol., 2020, 16: 673-688

[290] Kauther MD, Xu J, Wedemeyer C. Alpha-calcitonin gene-related peptide can reverse the catabolic influence of UHMWPE particles on RANKL expression in primary human osteoblasts. Int. J. Biol. Sci., 2010, 6: 525-536

[291] Lotz EM, Berger MB, Boyan BD, Schwartz Z. Regulation of mesenchymal stem cell differentiation on microstructured titanium surfaces by semaphorin 3A. Bone, 2020, 134: 115260

[292] Bely AE, Nyberg KG. Evolution of animal regeneration: re-emergence of a field. Trends Ecol. Evol., 2010, 25: 161-170

[293] Neff EP. What is a lab animal? Lab Anim. (NY), 2018, 47: 223-227

[294] Shaw TJ, Osborne M, Ponte G, Fiorito G, Andrews PLR. Mechanisms of wound closure following acute arm injury in Octopus vulgaris. Zool. Lett., 2016, 2: 8

[295] Emig CC. L’histogenèse régénératrice chez les phoronidiens. Wilhelm. Roux’ Arch Entwickl Mech Org, 1973, 173: 235-248

[296] Farkas JE, Monaghan JR. A brief history of the study of nerve dependent regeneration. Neurogenesis (Austin), 2017, 4: e1302216

Funding

Research Grants Council, University Grants Committee (RGC, UGC)(14120118, 14108720, C7030-18G, T13-402/17-N and AoE/M-402/20)

Department of Science and Technology of Hubei Province (No. 2020BCB004) and the Wuhan Union Hospital "Pharmaceutical Technology nursing" special fund (No. 2019xhyn021).

National Natural Science Foundation of China (National Science Foundation of China)(82002313 and 82072444)

National Key Research & Development Program of China (2021YFA1101503, 2018YFC2001502 and 2018YFB1105705)