Zhu S, Chen W, Masson A, Li YP. Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis. Cell Discov. 2024;10(1):71.
Google Scholar
Xiong Y, Mi BB, Lin Z, Hu YQ, Yu L, Zha KK, et al. The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity. Mil Med Res. 2022;9(1):65.
Google Scholar
Zhao Y, Peng X, Wang Q, Zhang Z, Wang L, Xu Y, et al. Crosstalk between the neuroendocrine system and bone homeostasis. Endocr Rev. 2024;45(1):95–124.
Google Scholar
Wang L, You X, Lotinun S, Zhang L, Wu N, Zou W. Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk. Nat Commun. 2020;11(1):282.
Google Scholar
Li X, Liang T, Dai B, Chang L, Zhang Y, Hu S, et al. Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment. J Clin Invest. 2024;134(10):e166795.
Google Scholar
Salari N, Ghasemi H, Mohammadi L, Behzadi MH, Rabieenia E, Shohaimi S, et al. The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis. J Orthop Surg Res. 2021;16(1):609.
Google Scholar
Foessl I, Dimai HP, Obermayer-Pietsch B. Long-term and sequential treatment for osteoporosis. Nat Rev Endocrinol. 2023;19(9):520–33.
Google Scholar
Josephson CB, Gonzalez-Izquierdo A, Denaxas S, Sajobi TT, Klein KM, Wiebe S. Independent associations of incident epilepsy and enzyme-inducing and non-enzyme-inducing antiseizure medications with the development of osteoporosis. JAMA Neurol. 2023;80(8):843–50.
Google Scholar
Zhen G, Guo Q, Li Y, Wu C, Zhu S, Wang R, et al. Mechanical stress determines the configuration of TGFβ activation in articular cartilage. Nat Commun. 2021;12(1):1706.
Google Scholar
Walsh DA, McWilliams DF. Mechanisms, impact and management of pain in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10(10):581–92.
Google Scholar
Gelber AC. Knee osteoarthritis. Ann Intern Med. 2024;177(9):ITC129–44.
Google Scholar
Chen W, Mehlkop O, Scharn A, Nolte H, Klemm P, Henschke S, et al. Nutrient-sensing AgRP neurons relay control of liver autophagy during energy deprivation. Cell Metab. 2023;35(5):786-806.e13.
Google Scholar
Hsueh B, Chen R, Jo Y, Tang D, Raffiee M, Kim YS, et al. Cardiogenic control of affective behavioural state. Nature. 2023;615(7951):292–9.
Google Scholar
Servin-Vences MR, Lam RM, Koolen A, Wang Y, Saade DN, Loud M, et al. PIEZO2 in somatosensory neurons controls gastrointestinal transit. Cell. 2023;186(16):3386-99.e15.
Google Scholar
Meng JJ, Shen JW, Li G, Ouyang CJ, Hu JX, Li ZS, et al. Light modulates glucose metabolism by a retina-hypothalamus-brown adipose tissue axis. Cell. 2023;186(2):398-412.e17.
Google Scholar
Teratani T, Mikami Y, Nakamoto N, Suzuki T, Harada Y, Okabayashi K, et al. The liver-brain-gut neural arc maintains the T-reg) cell niche in the gut. Nature. 2020;585(7826):591–6.
Google Scholar
Chang RB, Strochlic DE, Williams EK, Umans BD, Liberles SD. Vagal sensory neuron subtypes that differentially control breathing. Cell. 2015;161(3):622–33.
Google Scholar
Hohmann EL, Elde RP, Rysavy JA, Einzig S, Gebhard RL. Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers. Science. 1986;232(4752):868–71.
Google Scholar
Karsenty G, Khosla S. The crosstalk between bone remodeling and energy metabolism: a translational perspective. Cell Metab. 2022;34(6):805–17.
Google Scholar
Deng AF, Wang FX, Wang SC, Zhang YZ, Bai L, Su JC. Bone-organ axes: bidirectional crosstalk. Mil Med Res. 2024;11(1):37.
Google Scholar
Kim JG, Sun BH, Dietrich MO, Koch M, Yao GQ, Diano S, et al. AgRP neurons regulate bone mass. Cell Rep. 2015;13(1):8–14.
Google Scholar
Enriquez RF, Lee NJ, Herzog H. AgRP signalling negatively regulates bone mass. J Neuroendocrinol. 2021;33(5):e12978.
Google Scholar
Idelevich A, Sato K, Nagano K, Rowe G, Gori F, Baron R. Neuronal hypothalamic regulation of body metabolism and bone density is galanin dependent. J Clin Invest. 2018;128(6):2626–41.
Google Scholar
Sasanuma H, Nakata M, Parmila K, Nakae J, Yada T. PDK1-FoxO1 pathway in AgRP neurons of arcuate nucleus promotes bone formation via GHRH-GH-IGF1 axis. Mol Metab. 2017;6(5):428–39.
Google Scholar
Herber CB, Krause WC, Wang L, Bayrer JR, Li A, Schmitz M, et al. Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones. Nat Commun. 2019;10(1):163.
Google Scholar
Farman HH, Windahl SH, Westberg L, Isaksson H, Egecioglu E, Schele E, et al. Female mice lacking estrogen receptor-alpha in hypothalamic proopiomelanocortin (POMC) neurons display enhanced estrogenic response on cortical bone mass. Endocrinology. 2016;157(8):3242–52.
Google Scholar
Baldock PA, Lee NJ, Driessler F, Lin S, Allison S, Stehrer B, et al. Neuropeptide Y knockout mice reveal a central role of NPY in the coordination of bone mass to body weight. PLoS One. 2009;4(12):e8415.
Google Scholar
Lee NJ, Qi Y, Enriquez RF, Ip CK, Herzog H. Lack of NPY in neurotensin neurons leads to a lean phenotype. Neuropeptides. 2020;80:101994.
Google Scholar
Idelevich A, Sato K, Avihai B, Nagano K, Galien A, Rowe G, et al. Both NPY-expressing and CART-expressing neurons increase energy expenditure and trabecular bone mass in response to AP1 antagonism, but have opposite effects on bone resorption. J Bone Miner Res. 2020;35(6):1107–18.
Google Scholar
Lee NJ, Clarke IM, Zengin A, Enriquez RF, Nagy V, Penninger JM, et al. RANK deletion in neuropeptide Y neurones attenuates oestrogen deficiency-related bone loss. J Neuroendocrinol. 2019;31(2):e12687.
Google Scholar
Oury F, Yadav VK, Wang Y, Zhou B, Liu XS, Guo XE, et al. CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons. Genes Dev. 2010;24(20):2330–42.
Google Scholar
Yadav VK, Oury F, Suda N, Liu ZW, Gao XB, Confavreux C, et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell. 2009;138(5):976–89.
Google Scholar
Yang F, Liu Y, Chen S, Dai Z, Yang D, Gao D, et al. A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress-induced bone loss. J Clin Invest. 2020;130(12):6539–54.
Google Scholar
Sun JS, Yang DJ, Kinyua AW, Yoon SG, Seong JK, Kim J, et al. Ventromedial hypothalamic primary cilia control energy and skeletal homeostasis. J Clin Invest. 2021;131(1):e138107.
Google Scholar
Zhang Z, Park JW, Ahn IS, Diamante G, Sivakumar N, Arneson D, et al. Estrogen receptor alpha in the brain mediates tamoxifen-induced changes in physiology in mice. Elife. 2021;10:e63333.
Google Scholar
Shiek AB, Petty SJ, Gorelik A, O’Brien TJ, Hill KD, Christie JJ, et al. Bone loss with antiepileptic drug therapy: a twin and sibling study. Osteoporos Int. 2017;28(9):2591–600.
Google Scholar
Kajimura D, Lee HW, Riley KJ, Arteaga-Solis E, Ferron M, Zhou B, et al. Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. Cell Metab. 2013;17(6):901–15.
Google Scholar
Luo N, Mosialou I, Capulli M, Bisikirska B, Lin CS, Huang YY, et al. A neuronal action of sirtuin 1 suppresses bone mass in young and aging mice. J Clin Invest. 2022;132(23):e152868.
Google Scholar
Liu N, Li B, Zhang L, Yang D, Yang F. Basolateral amygdala mediates central mechanosensory feedback of musculoskeletal system. Front Mol Neurosci. 2022;15:834980.
Google Scholar
Shao J, Gao DS, Liu YH, Chen SP, Liu N, Zhang L, et al. Cav3.1-driven bursting firing in ventromedial hypothalamic neurons exerts dual control of anxiety-like behavior and energy expenditure. Mol Psychiatry. 2022;27(6):2901–13.
Google Scholar
Velasco ER, Florido A, Flores A, Senabre E, Gomez-Gomez A, Torres A, et al. PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus. Nat Commun. 2022;13(1):4374.
Google Scholar
Ye H, Feng B, Wang C, Saito K, Yang Y, Ibrahimi L, et al. An estrogen-sensitive hypothalamus-midbrain neural circuit controls thermogenesis and physical activity. Sci Adv. 2022;8(3):0185.
Google Scholar
Kim KW, Sohn JW, Kohno D, Xu Y, Williams K, Elmquist JK. SF-1 in the ventral medial hypothalamic nucleus: a key regulator of homeostasis. Mol Cell Endocrinol. 2011;336(1–2):219–23.
Google Scholar
Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, Tang V, et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron. 2006;49(2):191–203.
Google Scholar
Hino K, Nifuji A, Morinobu M, Tsuji K, Ezura Y, Nakashima K, et al. Unloading-induced bone loss was suppressed in gold-thioglucose treated mice. J Cell Biochem. 2006;99(3):845–52.
Google Scholar
Bab IA, Yirmiya R. Depression and bone mass. Ann NY Acad Sci. 2010;1192:170–5.
Google Scholar
Liu Y, Shao J, Gao D, Zhang L, Yang F. Astrocytes in the ventromedial hypothalamus involve chronic stress-induced anxiety and bone loss in mice. Neural Plast. 2021;2021:7806370.
Google Scholar
Engstrom RL, Pereira MMA, de Solis AJ, Fenselau H, Bruning JC. NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons. Nat Commun. 2020;11(1):442.
Google Scholar
Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411(6836):480–4.
Google Scholar
Brown CH. Magnocellular neurons and posterior pituitary function. Compr Physiol. 2016;6(4):1701–41.
Google Scholar
Oti T, Satoh K, Uta D, Nagafuchi J, Tateishi S, Ueda R, et al. Oxytocin influences male sexual activity via non-synaptic axonal release in the spinal cord. Curr Biol. 2021;31(1):103-14.e5.
Google Scholar
Ryan PJ, Ross SI, Campos CA, Derkach VA, Palmiter RD. Oxytocin-receptor-expressing neurons in the parabrachial nucleus regulate fluid intake. Nat Neurosci. 2017;20(12):1722–33.
Google Scholar
Fenselau H, Campbell JN, Verstegen AM, Madara JC, Xu J, Shah BP, et al. A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nat Neurosci. 2017;20(1):42–51.
Google Scholar
Sun L, Lizneva D, Ji Y, Colaianni G, Hadelia E, Gumerova A, et al. Oxytocin regulates body composition. Proc Natl Acad Sci U S A. 2019;116(52):26808–15.
Google Scholar
Tamma R, Sun L, Cuscito C, Lu P, Corcelli M, Li J, et al. Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia. Proc Natl Acad Sci U S A. 2013;110(46):18644–9.
Google Scholar
Santos LFG, Fernandes-Breitenbach F, Silva RAS, Santos DR, Peres-Ueno MJ, Ervolino E, et al. The action of oxytocin on the bone of senescent female rats. Life Sci. 2022;297:120484.
Google Scholar
Zhang L, Liu N, Shao J, Gao D, Liu Y, Zhao Y, et al. Bidirectional control of parathyroid hormone and bone mass by subfornical organ. Neuron. 2023;111(12):1914-32.e6.
Google Scholar
Janak PH, Tye KM. From circuits to behaviour in the amygdala. Nature. 2015;517(7534):284–92.
Google Scholar
Pahk K, Kwon HW, Joung C, Kim S. Stress-related amygdala metabolic activity is associated with low bone mineral density in postmenopausal women: a pilot 18F-FDG PET/CT study. Front Endocrinol (Lausanne). 2021;12:719265.
Google Scholar
Seldeen KL, Halley PG, Volmar CH, Rodriguez MA, Hernandez M, Pang M, et al. Neuropeptide Y Y2 antagonist treated ovariectomized mice exhibit greater bone mineral density. Neuropeptides. 2018;67:45–55.
Google Scholar
Poe GR, Foote S, Eschenko O, Johansen JP, Bouret S, Aston-Jones G, et al. Locus coeruleus: a new look at the blue spot. Nat Rev Neurosci. 2020;21(11):644–59.
Google Scholar
Kim SM, Taneja C, Perez-Pena H, Ryu V, Gumerova A, Li W, et al. Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass. Proc Natl Acad Sci U S A. 2020;117(25):14386–94.
Google Scholar
Wan QQ, Qin WP, Ma YX, Shen MJ, Li J, Zhang ZB, et al. Crosstalk between bone and nerves within bone. Adv Sci (Weinh). 2021;8(7):2003390.
Google Scholar
Tavares-Ferreira D, Shiers S, Ray PR, Wangzhou A, Jeevakumar V, Sankaranarayanan I, et al. Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors. Sci Transl Med. 2022;14(632):8186.
Google Scholar
Tao R, Mi B, Hu Y, Lin S, Xiong Y, Lu X, et al. Hallmarks of peripheral nerve function in bone regeneration. Bone Res. 2023;11(1):6.
Google Scholar
Jimenez-Andrade JM, Mantyh WG, Bloom AP, Xu H, Ferng AS, Dussor G, et al. A phenotypically restricted set of primary afferent nerve fibers innervate the bone versus skin: therapeutic opportunity for treating skeletal pain. Bone. 2010;46(2):306–13.
Google Scholar
Mach DB, Rogers SD, Sabino MC, Luger NM, Schwei MJ, Pomonis JD, et al. Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience. 2002;113(1):155–66.
Google Scholar
Bjurholm A, Kreicbergs A, Brodin E, Schultzberg M. Substance P- and CGRP-immunoreactive nerves in bone. Peptides. 1988;9(1):165–71.
Google Scholar
Castaneda-Corral G, Jimenez-Andrade JM, Bloom AP, Taylor RN, Mantyh WG, Kaczmarska MJ, 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.
Google Scholar
Li WW, Guo TZ, Liang DY, Sun Y, Kingery WS, Clark JD. Substance P signaling controls mast cell activation, degranulation, and nociceptive sensitization in a rat fracture model of complex regional pain syndrome. Anesthesiology. 2012;116(4):882–95.
Google Scholar
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(3):469–80.
Google Scholar
Chartier SR, Mitchell SA, Majuta LA, Mantyh PW. Immunohistochemical localization of nerve growth factor, tropomyosin receptor kinase A, and p75 in the bone and articular cartilage of the mouse femur. Mol Pain. 2017;13:1744806917745465.
Google Scholar
Imai S, Matsusue Y. Neuronal regulation of bone metabolism and anabolism: calcitonin gene-related peptide-, substance P-, and tyrosine hydroxylase-containing nerves and the bone. Microsc Res Tech. 2002;58(2):61–9.
Google Scholar
Ahmed M, Bjurholm A, Kreicbergs A, Schultzberg M, Neuropeptide Y. tyrosine hydroxylase and vasoactive intestinal polypeptide-immunoreactive nerve fibers in the vertebral bodies, discs, dura mater, and spinal ligaments of the rat lumbar spine. Spine (Phila Pa 1976). 1993;18(2):268–73.
Google Scholar
Bjurholm A, Kreicbergs A, Terenius L, Goldstein M, Schultzberg M. Neuropeptide Y-, tyrosine hydroxylase- and vasoactive intestinal polypeptide-immunoreactive nerves in bone and surrounding tissues. J Auton Nerv Syst. 1988;25(2–3):119–25.
Google Scholar
Recalde A, Richart A, Guerin C, Cochain C, Zouggari Y, Yin KH, et al. Sympathetic nervous system regulates bone marrow-derived cell egress through endothelial nitric oxide synthase activation: role in postischemic tissue remodeling. Arterioscler Thromb Vasc Biol. 2012;32(3):643–53.
Google Scholar
Bjurholm A. Neuroendocrine peptides in bone. Int Orthop. 1991;15(4):325–9.
Google Scholar
Huang T, Hu J, Wang B, Nie Y, Geng J, Cheng L. Tlx3 controls cholinergic transmitter and Peptide phenotypes in a subset of prenatal sympathetic neurons. J Neurosci. 2013;33(26):10667–75.
Google Scholar
Asmus SE, Parsons S, Landis SC. Developmental changes in the transmitter properties of sympathetic neurons that innervate the periosteum. J Neurosci. 2000;20(4):1495–504.
Google Scholar
Gadomski S, Fielding C, Garcia-Garcia A, Korn C, Kapeni C, Ashraf S, et al. A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise. Cell Stem Cell. 2022;29(4):528-44.e9.
Google Scholar
Halder N, Lal G. Cholinergic system and its therapeutic importance in inflammation and autoimmunity. Front Immunol. 2021;12:660342.
Google Scholar
Ottaviani MM, Macefield VG. Structure and functions of the vagus nerve in mammals. Compr Physiol. 2022;12(4):3989–4037.
Google Scholar
Bajayo A, Bar A, Denes A, Bachar M, Kram V, Attar-Namdar M, et al. Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual. Proc Natl Acad Sci U S A. 2012;109(38):15455–60.
Google Scholar
Gajda M, Litwin JA, Tabarowski Z, Zagolski O, Cichocki T, Timmermans JP, et al. Development of rat tibia innervation: colocalization of autonomic nerve fiber markers with growth-associated protein 43. Cells Tissues Organs. 2010;191(6):489–99.
Google Scholar
Artico M, Bosco S, Cavallotti C, Agostinelli E, Giuliani-Piccari G, Sciorio S, et al. Noradrenergic and cholinergic innervation of the bone marrow. Int J Mol Med. 2002;10(1):77–80.
Google Scholar
Hoff AO, Catala-Lehnen P, Thomas PM, Priemel M, Rueger JM, Nasonkin I, et al. Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene. J Clin Invest. 2002;110(12):1849–57.
Google Scholar
Schinke T, Liese S, Priemel M, Haberland M, Schilling AF, Catala-Lehnen P, et al. Decreased bone formation and osteopenia in mice lacking alpha-calcitonin gene-related peptide. J Bone Miner Res. 2004;19(12):2049–56.
Google Scholar
Tuzmen C, Campbell PG. Crosstalk between neuropeptides SP and CGRP in regulation of BMP2-induced bone differentiation. Connect Tissue Res. 2018;59(sup1):81–90.
Google Scholar
Li H, Qu J, Zhu H, Wang J, He H, Xie X, et al. Corrigendum: CGRP regulates the age-related switch between osteoblast and adipocyte differentiation. Front Cell Dev Biol. 2021;9:715740.
Google Scholar
Liu X, Liu H, Xiong Y, Yang L, Wang C, Zhang R, et al. Postmenopausal osteoporosis is associated with the regulation of SP, CGRP, VIP, and NPY. Biomed Pharmacother. 2018;104:742–50.
Google Scholar
Zhang RH, Zhang XB, Lu YB, Hu YC, Chen XY, Yu DC, et al. Calcitonin gene-related peptide and brain-derived serotonin are related to bone loss in ovariectomized rats. Brain Res Bull. 2021;176:85–92.
Google Scholar
Appelt J, Baranowsky A, Jahn D, Yorgan T, Kohli P, Otto E, et al. The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing. EBioMedicine. 2020;59:102970.
Google Scholar
Wee NKY, Novak S, Ghosh D, Root SH, Dickerson IM, Kalajzic I. Inhibition of CGRP signaling impairs fracture healing in mice. J Orthop Res. 2023;41(6):1228–39.
Google Scholar
Zhang Y, Xu J, Ruan YC, Yu MK, O’Laughlin M, Wise H, et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nat Med. 2016;22(10):1160–9.
Google Scholar
Mi J, Xu JK, Yao Z, Yao H, Li Y, He X, et al. Implantable electrical stimulation at dorsal root ganglions accelerates osteoporotic fracture healing via calcitonin gene-related peptide. Adv Sci (Weinh). 2022;9(1):e2103005.
Google Scholar
Tomlinson RE, Li Z, Zhang Q, Goh BC, Li Z, Thorek DLJ, et al. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Rep. 2016;16(10):2723–35.
Google Scholar
Tower RJ, Li Z, Cheng YH, Wang XW, Rajbhandari L, Zhang Q, 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 U S A. 2021;118(42):e2103087118.
Google Scholar
Tomlinson RE, Li Z, Li Z, Minichiello L, Riddle RC, Venkatesan A, et al. NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in mice. Proc Natl Acad Sci U S A. 2017;114(18):E3632–41.
Google Scholar
Wuertz-Kozak K, Roszkowski M, Cambria E, Block A, Kuhn GA, Abele T, et al. Effects of early life stress on bone homeostasis in mice and humans. Int J Mol Sci. 2020;21(18):6634.
Google Scholar
Wang Y, Yang K, Li G, Liu R, Liu J, Li J, et al. p75NTR-/- mice exhibit an alveolar bone loss phenotype and inhibited PI3K/Akt/β-catenin pathway. Cell Prolif. 2020;53(4):e12800.
Google Scholar
Levi B. “TrkA”cking why “no pain, no gain” is the rule for bone formation. Sci Transl Med. 2017;9(389):3780.
Google Scholar
Nencini S, Ringuet M, Kim DH, Chen YJ, Greenhill C, Ivanusic JJ. Mechanisms of nerve growth factor signaling in bone nociceptors and in an animal model of inflammatory bone pain. Mol Pain. 2017;13:1744806917697011.
Google Scholar
Li Z, Meyers CA, Chang L, Lee S, Li Z, Tomlinson R, et al. Fracture repair requires TrkA signaling by skeletal sensory nerves. J Clin Invest. 2019;129(12):5137–50.
Google Scholar
Xu J, Li Z, Tower RJ, Negri S, Wang Y, Meyers CA, et al. NGF-p75 signaling coordinates skeletal cell migration during bone repair. Sci Adv. 2022;8(11):5716.
Google Scholar
Meyers CA, Lee S, Sono T, Xu J, Negri S, Tian Y, et al. A neurotrophic mechanism directs sensory nerve transit in cranial bone. Cell Rep. 2020;31(8):107696.
Google Scholar
Johnstone MR, Brady RD, Schuijers JA, Church JE, Orr D, Quinn JMW, et al. The selective TrkA agonist, gambogic amide, promotes osteoblastic differentiation and improves fracture healing in mice. J Musculoskelet Neuronal Interact. 2019;19(1):94–103.
Google Scholar
Zhao L, Lai Y, Jiao H, Huang J. Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints. Nat Commun. 2024;15(1):3225.
Google Scholar
Zhou XF. Peripheral projections of primary sensory neurons immunoreactive for brain-derived neurotrophic factor. Neurosci Lett. 1999;261(3):151–4.
Google Scholar
Podyma B, Parekh K, Guler AD, Deppmann CD. Metabolic homeostasis via BDNF and its receptors. Trends Endocrinol Metab. 2021;32(7):488–99.
Google Scholar
Guo Y, Dong SS, Chen XF, Jing YA, Yang M, Yan H, et al. Integrating epigenomic elements and GWASs identifies BDNF gene affecting bone mineral density and osteoporotic fracture risk. Sci Rep. 2016;6(1):30558.
Google Scholar
Li H, Fu M, Gao J, Fu J, Li T, Niu G. Genetic association between bone mineral density and the fracture of distal radius: a case-control study. Medicine (Baltimore). 2021;100(36):e27116.
Google Scholar
Xiong J, Liao J, Liu X, Zhang Z, Adams J, Pacifici R, et al. A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin. Nat Commun. 2022;13(1):4820.
Google Scholar
Xue F, Zhao Z, Gu Y, Han J, Ye K, Zhang Y. 7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis. Elife. 2021;10:e64872.
Google Scholar
Asaumi K, Nakanishi T, Asahara H, Inoue H, Takigawa M. Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone. 2000;26(6):625–33.
Google Scholar
Zhang Z, Zhang Y, Zhou Z, Shi H, Qiu X, Xiong J, et al. BDNF regulates the expression and secretion of VEGF from osteoblasts via the TrkB/ERK1/2 signaling pathway during fracture healing. Mol Med Rep. 2017;15(3):1362–7.
Google Scholar
Zhang Z, Hu P, Wang Z, Qiu X, Chen Y. BDNF promoted osteoblast migration and fracture healing by up-regulating integrin beta1 via TrkB-mediated ERK1/2 and Akt signalling. J Cell Mol Med. 2020;24(18):10792–802.
Google Scholar
Johnstone MR, Brady RD, Church JE, Orr D, McDonald SJ, Grills BL. The TrkB agonist, 7,8-dihydroxyflavone, impairs fracture healing in mice. J Musculoskelet Neuronal Interact. 2021;21(2):263–71.
Google Scholar
Xiao J, Yu W, Wang X, Wang B, Chen J, Liu Y, et al. Correlation between neuropeptide distribution, cancellous bone microstructure and joint pain in postmenopausal women with osteoarthritis and osteoporosis. Neuropeptides. 2016;56:97–104.
Google Scholar
Offley SC, Guo TZ, Wei T, Clark JD, Vogel H, Lindsey DP, et al. Capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity. J Bone Miner Res. 2005;20(2):257–67.
Google Scholar
Zheng XF, Zhao ED, He JY, Zhang YH, Jiang SD, Jiang LS. Inhibition of substance P signaling aggravates the bone loss in ovariectomy-induced osteoporosis. Prog Biophys Mol Biol. 2016;122(2):112–21.
Google Scholar
Piao J, Park JS, Hwang DY, Son Y, Hong HS. Substance P blocks ovariectomy-induced bone loss by modulating inflammation and potentiating stem cell function. Aging (Albany NY). 2020;12(20):20753–77.
Google Scholar
Kim D, Piao J, Park JS, Lee D, Hwang DY, Hong HS. Substance P-mediated vascular protection ameliorates bone loss. Oxid Med Cell Longev. 2023;2023:9903336.
Google Scholar
Niedermair T, Kuhn V, Doranehgard F, Stange R, Wieskotter B, Beckmann J, 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.
Google Scholar
Wang L, Hou S, Sabsovich I, Guo TZ, Wei T, Kingery WS. Mice lacking substance P have normal bone modeling but diminished bone formation, increased resorption, and accelerated osteopenia with aging. Bone. 2021;144:115806.
Google Scholar
Wedemeyer C, Neuerburg C, Pfeiffer A, Heckelei A, von Knoch F, Hilken G, et al. Polyethylene particle-induced bone resorption in substance P-deficient mice. Calcif Tissue Int. 2007;80(4):268–74.
Google Scholar
Li J, Ahmed M, Bergstrom J, Ackermann P, Stark A, Kreicbergs A. Occurrence of substance P in bone repair under different load comparison of straight and angulated fracture in rat tibia. J Orthop Res. 2010;28(12):1643–50.
Google Scholar
Hofman M, Rabenschlag F, Andruszkow H, Andruszkow J, Mockel D, Lammers T, et al. Effect of neurokinin-1-receptor blockage on fracture healing in rats. Sci Rep. 2019;9(1):9744.
Google Scholar
Niedermair T, Straub RH, Brochhausen C, Grassel S. Impact of the sensory and sympathetic nervous system on fracture healing in ovariectomized mice. Int J Mol Sci. 2020;21(2):405.
Google Scholar
Amirthalingam S, Lee SS, Rajendran AK, Kim I, Hwang NS, Rangasamy J. Addition of lactoferrin and substance P in a chitin/PLGA-CaSO(4) hydrogel for regeneration of calvarial bone defects. Mater Sci Eng C Mater Biol Appl. 2021;126:112172.
Google Scholar
Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell. 2002;111(3):305–17.
Google Scholar
Schlienger RG, Kraenzlin ME, Jick SS, Meier CR. Use of beta-blockers and risk of fractures. JAMA. 2004;292(11):1326–32.
Google Scholar
Treyball A, Bergeron AC, Brooks DJ, Langlais AL, Hashmi H, Nagano K, et al. Propranolol promotes bone formation and limits resorption through novel mechanisms during anabolic parathyroid hormone treatment in female C57BL/6J mice. J Bone Miner Res. 2022;37(5):954–71.
Google Scholar
Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 2005;434(7032):514–20.
Google Scholar
Pierroz DD, Bonnet N, Bianchi EN, Bouxsein ML, Baldock PA, Rizzoli R, et al. Deletion of beta-adrenergic receptor 1, 2, or both leads to different bone phenotypes and response to mechanical stimulation. J Bone Miner Res. 2012;27(6):1252–62.
Google Scholar
Alves BAE, Balera BVG, Patrocinio MS, Ballassoni BB, Tfaile FSC, Penha OSH. β1-adrenergic receptor but not β2 mediates osteogenic differentiation of bone marrow mesenchymal stem cells in normotensive and hypertensive rats. Eur J Pharmacol. 2021;911:174515.
Google Scholar
Khosla S, Drake MT, Volkman TL, Thicke BS, Achenbach SJ, Atkinson EJ, et al. Sympathetic beta1-adrenergic signaling contributes to regulation of human bone metabolism. J Clin Invest. 2018;128(11):4832–42.
Google Scholar
Togari A. Adrenergic regulation of bone metabolism: possible involvement of sympathetic innervation of osteoblastic and osteoclastic cells. Microsc Res Tech. 2002;58(2):77–84.
Google Scholar
Fonseca TL, Jorgetti V, Costa CC, Capelo LP, Covarrubias AE, Moulatlet AC, et al. Double disruption of α2A- and α2C-adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype. J Bone Miner Res. 2011;26(3):591–603.
Google Scholar
Tanaka K, Hirai T, Kodama D, Kondo H, Hamamura K, Togari A. alpha1B -Adrenoceptor signalling regulates bone formation through the up-regulation of CCAAT/enhancer-binding protein delta expression in osteoblasts. Br J Pharmacol. 2016;173(6):1058–69.
Google Scholar
McDonald SJ, Dooley PC, McDonald AC, Djouma E, Schuijers JA, Ward AR, et al. α(1) adrenergic receptor agonist, phenylephrine, actively contracts early rat rib fracture callus ex vivo. J Orthop Res. 2011;29(5):740–5.
Google Scholar
Feng J, Zhang C, Lischinsky JE, Jing M, Zhou J, Wang H, et al. A genetically encoded fluorescent sensor for rapid and specific in vivo detection of norepinephrine. Neuron. 2019;102(4):745-61.e8.
Google Scholar
Chen QC, Zhang Y. The role of NPY in the regulation of bone metabolism. Front Endocrinol (Lausanne). 2022;13:833485.
Google Scholar
Igwe JC, Jiang X, Paic F, Ma L, Adams DJ, Baldock PA, et al. Neuropeptide Y is expressed by osteocytes and can inhibit osteoblastic activity. J Cell Biochem. 2009;108(3):621–30.
Google Scholar
Lee NJ, Doyle KL, Sainsbury A, Enriquez RF, Hort YJ, Riepler SJ, et al. Critical role for Y1 receptors in mesenchymal progenitor cell differentiation and osteoblast activity. J Bone Miner Res. 2010;25(8):1736–47.
Google Scholar
Baldock PA, Allison SJ, Lundberg P, Lee NJ, Slack K, Lin EJ, et al. Novel role of Y1 receptors in the coordinated regulation of bone and energy homeostasis. J Biol Chem. 2007;282(26):19092–102.
Google Scholar
Lee NJ, Nguyen AD, Enriquez RF, Doyle KL, Sainsbury A, Baldock PA, et al. Osteoblast specific Y1 receptor deletion enhances bone mass. Bone. 2011;48(3):461–7.
Google Scholar
Allison SJ, Baldock P, Sainsbury A, Enriquez R, Lee NJ, Lin EJ, et al. Conditional deletion of hypothalamic Y2 receptors reverts gonadectomy-induced bone loss in adult mice. J Biol Chem. 2006;281(33):23436–44.
Google Scholar
Sainsbury A, Baldock PA, Schwarzer C, Ueno N, Enriquez RF, Couzens M, et al. Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice. Mol Cell Biol. 2003;23(15):5225–33.
Google Scholar
Long H, Ahmed M, Ackermann P, Stark A, Li J. Neuropeptide Y innervation during fracture healing and remodelling. A study of angulated tibial fractures in the rat. Acta Orthop. 2010;81(5):639–46.
Google Scholar
Alves CJ, Alencastre IS, Neto E, Ribas J, Ferreira S, Vasconcelos DM, et al. Bone injury and repair trigger central and peripheral NPY neuronal pathways. PLoS One. 2016;11(11):e0165465.
Google Scholar
Tang P, Duan C, Wang Z, Wang C, Meng G, Lin K, et al. NPY and CGRP inhibitor influence on ERK pathway and macrophage aggregation during fracture healing. Cell Physiol Biochem. 2017;41(4):1457–67.
Google Scholar
Sousa DM, McDonald MM, Mikulec K, Peacock L, Herzog H, Lamghari M, et al. Neuropeptide Y modulates fracture healing through Y1 receptor signaling. J Orthop Res. 2013;31(10):1570–8.
Google Scholar
Schwarzschild MA, Zigmond RE. Secretin and vasoactive intestinal peptide activate tyrosine hydroxylase in sympathetic nerve endings. J Neurosci. 1989;9(1):160–6.
Google Scholar
Shi L, Wang C, Yan Y, Wang G, Zhang J, Feng L, et al. Function study of vasoactive intestinal peptide on chick embryonic bone development. Neuropeptides. 2020;83:102077.
Google Scholar
Xie W, Li F, Han Y, Li Z, Xiao J. Neuropeptides are associated with pain threshold and bone microstructure in ovariectomized rats. Neuropeptides. 2020;81:101995.
Google Scholar
Wang W, Wang ZP, Huang CY, Chen YD, Yao WF, Shi BM. The neuropeptide vasoactive intestinal peptide levels in serum are inversely related to disease severity of postmenopausal osteoporosis: a cross-sectional study. Genet Test Mol Biomark. 2019;23(7):480–6.
Google Scholar
Grassel SG. The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology. Arthritis Res Ther. 2014;16(6):485.
Google Scholar
Lundberg P, Lie A, Bjurholm A, Lehenkari PP, Horton MA, Lerner UH, et al. Vasoactive intestinal peptide regulates osteoclast activity via specific binding sites on both osteoclasts and osteoblasts. Bone. 2000;27(6):803–10.
Google Scholar
Hohmann EL, Levine L, Tashjian AH Jr. Vasoactive intestinal peptide stimulates bone resorption via a cyclic adenosine 3’,5’-monophosphate-dependent mechanism. Endocrinology. 1983;112(4):1233–9.
Google Scholar
Shi L, Liu Y, Yang Z, Wu T, Lo HT, Xu J, et al. Vasoactive intestinal peptide promotes fracture healing in sympathectomized mice. Calcif Tissue Int. 2021;109(1):55–65.
Google Scholar
Shi L, Feng L, Zhu ML, Yang ZM, Wu TY, Xu J, 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(10):655–66.
Google Scholar
Ma Y, Elefteriou F. Brain-derived acetylcholine maintains peak bone mass in adult female mice. J Bone Miner Res. 2020;35(8):1562–71.
Google Scholar
Kauschke V, Kneffel M, Floel W, Hartmann S, Kampschulte M, Durselen L, et al. Bone status of acetylcholinesterase-knockout mice. Int Immunopharmacol. 2015;29(1):222–30.
Google Scholar
Haupt M, Kauschke V, Sender J, Kampschulte M, Kovtun A, Durselen L, et al. Bone status of adult female butyrylcholinesterase gene-deficient mice. Int Immunopharmacol. 2015;29(1):208–14.
Google Scholar
Kliemann K, Kneffel M, Bergen I, Kampschulte M, Langheinrich AC, Durselen L, et al. Quantitative analyses of bone composition in acetylcholine receptor M3R and alpha7 knockout mice. Life Sci. 2012;91(21–22):997–1002.
Google Scholar
Lips KS, Kneffel M, Willscheid F, Mathies FM, Kampschulte M, Hartmann S, et al. Altered ultrastructure, density and cathepsin K expression in bone of female muscarinic acetylcholine receptor M3 knockout mice. Int Immunopharmacol. 2015;29(1):201–7.
Google Scholar
Mito K, Sato Y, Kobayashi T, Miyamoto K, Nitta E, Iwama A, et al. The nicotinic acetylcholine receptor α7 subunit is an essential negative regulator of bone mass. Sci Rep. 2017;7:45597.
Google Scholar
Lips KS, Yanko O, Kneffel M, Panzer I, Kauschke V, Madzharova M, et al. Small changes in bone structure of female α7 nicotinic acetylcholine receptor knockout mice. BMC Musculoskelet Disord. 2015;16(1):5.
Google Scholar
Baumann L, Kauschke V, Vikman A, Durselen L, Krasteva-Christ G, Kampschulte M, et al. Deletion of nicotinic acetylcholine receptor alpha9 in mice resulted in altered bone structure. Bone. 2019;120:285–96.
Google Scholar
Eimar H, Alebrahim S, Manickam G, Al-Subaie A, Abu-Nada L, Murshed M, et al. Donepezil regulates energy metabolism and favors bone mass accrual. Bone. 2016;84:131–8.
Google Scholar
Al-Hamed FS, Maria OM, Phan J, Al Subaie A, Gao Q, Mansour A, et al. Postoperative administration of the acetylcholinesterase inhibitor, donepezil, interferes with bone healing and implant osseointegration in a rat model. Biomolecules. 2020;10(9):1318.
Google Scholar
Tamimi I, Ojea T, Sanchez-Siles JM, Rojas F, Martin I, Gormaz I, et al. Acetylcholinesterase inhibitors and the risk of hip fracture in Alzheimer’s disease patients: a case-control study. J Bone Miner Res. 2012;27(7):1518–27.
Google Scholar
Ogunwale AN, Colon-Emeric CS, Sloane R, Adler RA, Lyles KW, Lee RH. Acetylcholinesterase inhibitors are associated with reduced fracture risk among older veterans with dementia. J Bone Miner Res. 2020;35(3):440–5.
Google Scholar
Eimar H, Perez Lara A, Tamimi I, Marquez Sanchez P, Gormaz Talavera I, Rojas Tomba F, et al. Acetylcholinesterase inhibitors and healing of hip fracture in Alzheimer’s disease patients: a retrospective cohort study. J Musculoskelet Neuronal Interact. 2013;13(4):454–63.
Google Scholar
Erickson AG, Motta A, Kastriti ME, Edwards S, Coulpier F, Theoulle E, et al. Motor innervation directs the correct development of the mouse sympathetic nervous system. Nat Commun. 2024;15(1):7065.
Google Scholar
Buijs TJ, Vilar B, Tan CH, McNaughton PA. STIM1 and ORAI1 form a novel cold transduction mechanism in sensory and sympathetic neurons. EMBO J. 2023;42(3):e111348.
Google Scholar
Aalkjaer C, Nilsson H, De Mey JGR. Sympathetic and sensory-motor nerves in peripheral small arteries. Physiol Rev. 2021;101(2):495–544.
Google Scholar
Wang Y, Leung VH, Zhang Y, Nudell VS, Loud M, Servin-Vences MR, et al. The role of somatosensory innervation of adipose tissues. Nature. 2022;609(7927):569–74.
Google Scholar
Hu B, Lv X, Chen H, Xue P, Gao B, Wang X, et al. Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones. J Clin Invest. 2020;130(7):3483–98.
Google Scholar
Qi L, Iskols M, Shi D, Reddy P, Walker C, Lezgiyeva K, et al. A mouse DRG genetic toolkit reveals morphological and physiological diversity of somatosensory neuron subtypes. Cell. 2024;187(6):1508-26.e16.
Google Scholar
Brazill JM, Beeve AT, Craft CS, Ivanusic JJ, Scheller EL. Nerves in bone: evolving concepts in pain and anabolism. J Bone Miner Res. 2019;34(8):1393–406.
Google Scholar
Williams GA, Callon KE, Watson M, Costa JL, Ding Y, Dickinson M, et al. Skeletal phenotype of the leptin receptor-deficient db/db mouse. J Bone Miner Res. 2011;26(8):1698–709.
Google Scholar
Bartell SM, Rayalam S, Ambati S, Gaddam DR, Hartzell DL, Hamrick M, et al. Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice. J Bone Miner Res. 2011;26(8):1710–20.
Google Scholar
Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100(2):197–207.
Google Scholar
Hamrick MW, Ferrari SL. Leptin and the sympathetic connection of fat to bone. Osteoporos Int. 2008;19(7):905–12.
Google Scholar
Iwaniec UT, Boghossian S, Trevisiol CH, Wronski TJ, Turner RT, Kalra SP. Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats. J Bone Miner Res. 2011;26(7):1506–16.
Google Scholar
Yue R, Zhou BO, Shimada IS, Zhao Z, Morrison SJ. Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow. Cell Stem Cell. 2016;18(6):782–96.
Google Scholar
Jeffery EC, Mann TLA, Pool JA, Zhao Z, Morrison SJ. Bone marrow and periosteal skeletal stem/progenitor cells make distinct contributions to bone maintenance and repair. Cell Stem Cell. 2022;29(11):1547-61.e6.
Google Scholar
Wei Y, Wang L, Clark JC, Dass CR, Choong PF. Elevated leptin expression in a rat model of fracture and traumatic brain injury. J Pharm Pharmacol. 2008;60(12):1667–72.
Google Scholar
Garbe A, Graef F, Appelt J, Schmidt-Bleek K, Jahn D, Lunnemann T, et al. Leptin mediated pathways stabilize posttraumatic insulin and osteocalcin patterns after long bone fracture and concomitant traumatic brain injury and thus influence fracture healing in a combined murine trauma model. Int J Mol Sci. 2020;21(23):9144.
Google Scholar
Wang L, Tang X, Zhang H, Yuan J, Ding H, Wei Y. Elevated leptin expression in rat model of traumatic spinal cord injury and femoral fracture. J Spinal Cord Med. 2011;34(5):501–9.
Google Scholar
Brighton PJ, Szekeres PG, Willars GB. Neuromedin U and its receptors: structure, function, and physiological roles. Pharmacol Rev. 2004;56(2):231–48.
Google Scholar
Gianfagna F, Cugino D, Ahrens W, Bailey ME, Bammann K, Herrmann D, et al. Understanding the links among neuromedin U gene, beta2-adrenoceptor gene and bone health: an observational study in European children. PLoS One. 2013;8(8):e70632.
Google Scholar
Sato S, Hanada R, Kimura A, Abe T, Matsumoto T, Iwasaki M, et al. Central control of bone remodeling by neuromedin U. Nat Med. 2007;13(10):1234–40.
Google Scholar
Hsiao YT, Manikowski KJ, Snyder S, Griffin N, Orr AL, Hulsey EQ, et al. NMUR1 in the NMU-mediated regulation of bone remodeling. Life (Basel). 2021;11(10):1028.
Google Scholar
Cristino L, Bisogno T, Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol. 2020;16(1):9–29.
Google Scholar
Gunduz-Cinar O. The endocannabinoid system in the amygdala and modulation of fear. Prog Neuropsychopharmacol Biol Psychiatry. 2021;105:110116.
Google Scholar
Bara A, Ferland JN, Rompala G, Szutorisz H, Hurd YL. Cannabis and synaptic reprogramming of the developing brain. Nat Rev Neurosci. 2021;22(7):423–38.
Google Scholar
Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, et al. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci U S A. 2006;103(3):696–701.
Google Scholar
Tam J, Ofek O, Fride E, Ledent C, Gabet Y, Muller R, et al. Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling. Mol Pharmacol. 2006;70(3):786–92.
Google Scholar
Khalid AB, Goodyear SR, Ross RA, Aspden RM. Mechanical and material properties of cortical and trabecular bone from cannabinoid receptor-1-null Cnr1-/- mice. Med Eng Phys. 2016;38(10):1044–54.
Google Scholar
Sophocleous A, Marino S, Kabir D, Ralston SH, Idris AI. Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition. Aging Cell. 2017;16(5):1051–61.
Google Scholar
Kostrzewa M, Mahmoud AM, Verde R, Scotto di Carlo F, Gianfrancesco F, Piscitelli F, et al. Modulation of endocannabinoid ton6e in osteoblastic differentiation of MC3T3-E1 cells and in mouse bone tissue over time. Cells. 2021;10(5):1199.
Google Scholar
Xu A, Yang Y, Shao Y, Wu M, Sun Y. Activation of cannabinoid receptor type 2-induced osteogenic differentiation involves autophagy induction and p62-mediated Nrf2 deactivation. Cell Commun Signal. 2020;18(1):9.
Google Scholar
Kogan NM, Melamed E, Wasserman E, Raphael B, Breuer A, Stok KS, et al. Cannabidiol, a major non-psychotropic cannabis constituent enhances fracture healing and stimulates lysyl hydroxylase activity in osteoblasts. J Bone Miner Res. 2015;30(10):1905–13.
Google Scholar
Spencer NJ, Hu H. Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility. Nat Rev Gastroenterol Hepatol. 2020;17(6):338–51.
Google Scholar
Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355–66.
Google Scholar
Ducy P, Karsenty G. The two faces of serotonin in bone biology. J Cell Biol. 2010;191(1):7–13.
Google Scholar
Chabbi-Achengli Y, Coudert AE, Callebert J, Geoffroy V, Cote F, Collet C, et al. Decreased osteoclastogenesis in serotonin-deficient mice. Proc Natl Acad Sci U S A. 2012;109(7):2567–72.
Google Scholar
Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, et al. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat Med. 2010;16(3):308–12.
Google Scholar
Frost M, Andersen T, Gossiel F, Hansen S, Bollerslev J, van Hul W, et al. Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5. J Bone Miner Res. 2011;26(8):1721–8.
Google Scholar
Cui Y, Niziolek PJ, MacDonald BT, Zylstra CR, Alenina N, Robinson DR, et al. Lrp5 functions in bone to regulate bone mass. Nat Med. 2011;17(6):684–91.
Google Scholar
Sugisawa E, Takayama Y, Takemura N, Kondo T, Hatakeyama S, Kumagai Y, et al. RNA sensing by gut Piezo1 is essential for systemic serotonin synthesis. Cell. 2020;182(3):609-24.e21.
Google Scholar
Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC. The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation. FASEB J. 2008;22(2):418–27.
Google Scholar
Kode A, Mosialou I, Silva BC, Rached MT, Zhou B, Wang J, et al. FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin. J Clin Invest. 2012;122(10):3490–503.
Google Scholar
Brommage R, Liu J, Doree D, Yu W, Powell DR, Melissa YQ. Adult Tph2 knockout mice without brain serotonin have moderately elevated spine trabecular bone but moderately low cortical bone thickness. Bonekey Rep. 2015;4:718.
Google Scholar
Vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int. 2006;17(6):807–16.
Google Scholar
Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ 3rd. Psychotropic drug use and the risk of hip fracture. N Engl J Med. 1987;316(7):363–9.
Google Scholar
Liu B, Anderson G, Mittmann N, To T, Axcell T, Shear N. Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet. 1998;351(9112):1303–7.
Google Scholar
Bradaschia-Correa V, Josephson AM, Mehta D, Mizrahi M, Neibart SS, Liu C, et al. The selective serotonin reuptake inhibitor fluoxetine directly inhibits osteoblast differentiation and mineralization during fracture healing in mice. J Bone Miner Res. 2017;32(4):821–33.
Google Scholar
Lee S, Remark LH, Buchalter DB, Josephson AM, Wong MZ, Litwa HP, et al. Propranolol reverses impaired fracture healing response observed with selective serotonin reuptake inhibitor treatment. J Bone Miner Res. 2020;35(5):932–41.
Google Scholar
Ahmadian-Moghadam H, Sadat-Shirazi MS, Zarrindast MR. Cocaine- and amphetamine-regulated transcript (CART): a multifaceted neuropeptide. Peptides. 2018;110:56–77.
Google Scholar
Ahn JD, Dubern B, Lubrano-Berthelier C, Clement K, Karsenty G. Cart overexpression is the only identifiable cause of high bone mass in melanocortin 4 receptor deficiency. Endocrinology. 2006;147(7):3196–202.
Google Scholar
Singh MK, Elefteriou F, Karsenty G. Cocaine and amphetamine-regulated transcript may regulate bone remodeling as a circulating molecule. Endocrinology. 2008;149(8):3933–41.
Google Scholar
Gerrits H, Bakker NE, van de Ven-de LCJ, Bourgondien FG, Peddemors C, Litjens RH, et al. Gender-specific increase of bone mass by CART peptide treatment is ovary-dependent. J Bone Miner Res. 2011;26(12):2886–98.
Google Scholar
Khan S, Nobili L, Khatami R, Loddenkemper T, Cajochen C, Dijk DJ, et al. Circadian rhythm and epilepsy. Lancet Neurol. 2018;17(12):1098–108.
Google Scholar
Kojetin DJ, Burris TP. REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov. 2014;13(3):197–216.
Google Scholar
Hastings MH, Maywood ES, Brancaccio M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci. 2018;19(8):453–69.
Google Scholar
Yu S, Tang Q, Chen G, Lu X, Yin Y, Xie M, et al. Circadian rhythm modulates endochondral bone formation via MTR1/AMPKβ1/BMAL1 signaling axis. Cell Death Differ. 2022;29(4):874–87.
Google Scholar
Xu C, Ochi H, Fukuda T, Sato S, Sunamura S, Takarada T, et al. Circadian clock regulates bone resorption in mice. J Bone Miner Res. 2016;31(7):1344–55.
Google Scholar
Schilperoort M, Bravenboer N, Lim J, Mletzko K, Busse B, van Ruijven L, et al. Circadian disruption by shifting the light-dark cycle negatively affects bone health in mice. FASEB J. 2020;34(1):1052–64.
Google Scholar
Khor EC, Yulyaningsih E, Driessler F, Kovacic N, Wee NKY, Kulkarni RN, et al. The y6 receptor suppresses bone resorption and stimulates bone formation in mice via a suprachiasmatic nucleus relay. Bone. 2016;84:139–47.
Google Scholar
Meadows JD, Breuer JA, Lavalle SN, Hirschenberger MR, Patel MM, Nguyen D, et al. Deletion of Six3 in post-proliferative neurons produces weakened SCN circadian output, improved metabolic function, and dwarfism in male mice. Mol Metab. 2022;57:101431.
Google Scholar
Fu L, Patel MS, Bradley A, Wagner EF, Karsenty G. The molecular clock mediates leptin-regulated bone formation. Cell. 2005;122(5):803–15.
Google Scholar
Fu S, Kuwahara M, Uchida Y, Koudo S, Hayashi D, Shimomura Y, et al. Circadian production of melatonin in cartilage modifies rhythmic gene expression. J Endocrinol J Endocrinol. 2019. https://doi.org/10.1530/JOE-19-0022.
Google Scholar
Tsang K, Liu H, Yang Y, Charles JF, Ermann J. Defective circadian control in mesenchymal cells reduces adult bone mass in mice by promoting osteoclast function. Bone. 2019;121:172–80.
Google Scholar
Zhou X, Yu R, Long Y, Zhao J, Yu S, Tang Q, et al. BMAL1 deficiency promotes skeletal mandibular hypoplasia via OPG downregulation. Cell Prolif. 2018;51(5):e12470.
Google Scholar
Kawai M, Kinoshita S, Yamazaki M, Yamamoto K, Rosen CJ, Shimba S, et al. Intestinal clock system regulates skeletal homeostasis. JCI Insight. 2019;4(5):e121798.
Google Scholar
Ko FC, Jochum SB, Wilson BM, Adra A, Patel N, Lee H, et al. Colon epithelial cell-specific Bmal1 deletion impairs bone formation in mice. Bone. 2023;168:116650.
Google Scholar
Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science. 1994;264(5159):719–25.
Google Scholar
Yuan G, Hua B, Yang Y, Xu L, Cai T, Sun N, et al. The circadian gene clock regulates bone formation via PDIA3. J Bone Miner Res. 2017;32(4):861–71.
Google Scholar
Maronde E, Schilling AF, Seitz S, Schinke T, Schmutz I, van der Horst G, et al. The clock genes Period 2 and cryptochrome 2 differentially balance bone formation. PLoS One. 2010;5(7):e11527.
Google Scholar
Zheng B, Albrecht U, Kaasik K, Sage M, Lu W, Vaishnav S, et al. Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell. 2001;105(5):683–94.
Google Scholar
Meyer T, Kneissel M, Mariani J, Fournier B. In vitro and in vivo evidence for orphan nuclear receptor RORalpha function in bone metabolism. Proc Natl Acad Sci U S A. 2000;97(16):9197–202.
Google Scholar
Farr JN, Weivoda MM, Nicks KM, Fraser DG, Negley BA, Onken JL, et al. Osteoprotection through the deletion of the transcription factor rorbeta in mice. J Bone Miner Res. 2018;33(4):720–31.
Google Scholar
Masana MI, Sumaya IC, Becker-Andre M, Dubocovich ML. Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORbeta knockout. Am J Physiol Regul Integr Comp Physiol. 2007;292(6):R2357–67.
Google Scholar
Song C, Tan P, Zhang Z, Wu W, Dong Y, Zhao L, et al. REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation. FASEB J. 2018;32(6):3215–28.
Google Scholar
Qin W, Bauman WA, Cardozo CP. Evolving concepts in neurogenic osteoporosis. Curr Osteoporos Rep. 2010;8(4):212–8.
Google Scholar
Zaidi M, Yuen T, Kim SM. Pituitary crosstalk with bone, adipose tissue and brain. Nat Rev Endocrinol. 2023;19(12):708–21.
Google Scholar
Branemark PI. Osseointegration and its experimental background. J Prosthet Dent. 1983;50(3):399–410.
Google Scholar
Zhao X, Wu G, Zhang J, Yu Z, Wang J. Activation of CGRP receptor-mediated signaling promotes tendon-bone healing. Sci Adv. 2024;10(10):7380.
Google Scholar
Deng J, Cohen DJ, Redden J, McClure MJ, Boyan BD, Schwartz Z. Differential effects of neurectomy and botox-induced muscle paralysis on bone phenotype and titanium implant osseointegration. Bone. 2021;153:116145.
Google Scholar
Morinaga K, Sasaki H, Park S, Hokugo A, Okawa H, Tahara Y, et al. Neuronal PAS domain 2 (Npas2) facilitated osseointegration of titanium implant with rough surface through a neuroskeletal mechanism. Biomaterials. 2019;192:62–74.
Google Scholar
Zhou P, He F, Liu B, Wei S. Nerve electrical stimulation enhances osseointegration of implants in the beagle. Sci Rep. 2019;9(1):4916.
Google Scholar
Farina D, Vujaklija I, Branemark R, Bull AMJ, Dietl H, Graimann B, et al. Toward higher-performance bionic limbs for wider clinical use. Nat Biomed Eng. 2023;7(4):473–85.
Google Scholar
Ortiz-Catalan M, Mastinu E, Sassu P, Aszmann O, Branemark R. Self-contained neuromusculoskeletal arm prostheses. N Engl J Med. 2020;382(18):1732–8.
Google Scholar
Marrella A, Lee TY, Lee DH, Karuthedom S, Syla D, Chawla A, et al. Engineering vascularized and innervated bone biomaterials for improved skeletal tissue regeneration. Mater Today (Kidlington). 2018;21(4):362–76.
Google Scholar
Xu H, Tian F, Liu Y, Liu R, Li H, Gao X, et al. Magnesium malate-modified calcium phosphate bone cement promotes the repair of vertebral bone defects in minipigs via regulating CGRP. J Nanobiotechnology. 2024;22(1):368.
Google Scholar
Jing X, Xu C, Su W, Ding Q, Ye B, Su Y, et al. Photosensitive and conductive hydrogel induced innerved bone regeneration for infected bone defect repair. Adv Healthc Mater. 2023;12(3):e2201349.
Google Scholar
Rivera KO, Cuylear DL, Duke VR, O’Hara KM, Zhong JX, Elghazali NA, et al. Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair. Front Bioeng Biotechnol. 2023;11:1190371.
Google Scholar
Rivera KO, Russo F, Boileau RM, Tomlinson RE, Miclau T, Marcucio RS, et al. Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion. Sci Rep. 2020;10(1):22241.
Google Scholar
Haffner-Luntzer M, Foertsch S, Fischer V, Prystaz K, Tschaffon M, Modinger Y, et al. Chronic psychosocial stress compromises the immune response and endochondral ossification during bone fracture healing via β-AR signaling. Proc Natl Acad Sci U S A. 2019;116(17):8615–22.
Google Scholar
link