Abstract
The skeleton is no longer seen as a static, isolated, and mostly structural organ. Over the last two decades, a more complete picture of the multiple functions of the skeleton has emerged, and its interactions with a growing number of apparently unrelated organs have become evident. The skeleton not only reacts to mechanical loading and inflammatory, hormonal, and mineral challenges, but also acts of its own accord by secreting factors controlling the function of other tissues, including the kidney and possibly the pancreas and gonads. It is thus becoming widely recognized that it is by nature an endocrine organ, in addition to a structural organ and site of mineral storage and hematopoiesis. Consequently and by definition, bone homeostasis must be tightly regulated and integrated with the biology of other organs to maintain whole body homeostasis, and data uncovering the involvement of the central nervous system (CNS) in the control of bone remodeling support this concept. The sympathetic nervous system (SNS) represents one of the main links between the CNS and the skeleton, based on a number of anatomic, pharmacologic, and genetic studies focused on β-adrenergic receptor (βAR) signaling in bone cells. The goal of this report was to review the data supporting the role of the SNS and βAR signaling in the regulation of skeletal homeostasis.
Similar content being viewed by others
References
Ebell BB (1937) The Paprus Ebers: the greatest Egyptian medical document. Oxford University Press, London
Gros M (1846) La Disposition des nerfs des os. Bull Soc Anat Paris 21:369–372
Hayat M (2002) Factors affecting antigen retrieval. In: Hayat MA (ed) Microscopy, immunohistochemistry, and antigen retrieval methods for light and electron microscopy. Springer, pp 53–69
Shi SR, Key ME, Kalra KL (1991) Antigen retrieval in formalin-fixed, paraffin-embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. J Histochem Cytochem 39:741–748
de Castro F (1929) Quelques observations sur l’intervention du système nerveux autonome dans l’ossification. Innervation du tissu osseux et de la moelle osseuse. T. Travaux du Lab Rec Biol Univ Madrid 26:215
Castaneda-Corral G, Jimenez-Andrade JM, Bloom AP, Taylor RN, Mantyh WG, Kaczmarska MJ, Ghilardi JR, Mantyh PW (2011) The majority of myelinated and unmyelinated sensory nerve fibers that innervate bone express the tropomyosin receptor kinase A. Neuroscience 178:196–207
Bjurholm A, Kreicbergs A, Terenius L, Goldstein M, Schultzberg M (1988) Neuropeptide Y-, tyrosine hydroxylase- and vasoactive intestinal polypeptide-immunoreactive nerves in bone and surrounding tissues. J Auton Nerv Syst 25:119–125
Duncan CP, Shim SS (1977) J. Edouard Samson Address: the autonomic nerve supply of bone. An experimental study of the intraosseous adrenergic nervi vasorum in the rabbit. J Bone Jt Surg Br 59:323–330
Ohtori S, Inoue G, Koshi T, Ito T, Watanabe T, Yamashita M, Yamauchi K, Suzuki M, Doya H, Moriya H, Takahashi Y, Takahashi K (2007) Sensory innervation of lumbar vertebral bodies in rats. Spine 32:1498–1502
Mach DB, Rogers SD, Sabino MC, Luger NM, Schwei MJ, Pomonis JD, Keyser CP, Clohisy DR, Adams DJ, O’Leary P, Mantyh PW (2002) Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience 113:155–166
Mahns DA, Ivanusic JJ, Sahai V, Rowe MJ (2006) An intact peripheral nerve preparation for monitoring the activity of single, periosteal afferent nerve fibres. J Neurosci Methods 156:140–144
Fan W, Bouwense SA, Crawford R, Xiao Y (2010) Structural and cellular features in metaphyseal and diaphyseal periosteum of osteoporotic rats. J Mol Histol 41:51–60
Denes A, Boldogkoi Z, Uhereczky G, Hornyak A, Rusvai M, Palkovits M, Kovacs KJ (2005) Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience 134:947–963
Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell 111:305–317
Ring PA (1961) The influence of the nervous system upon the growth of bones. J Bone Jt Surg Br 43:121–140
Gajda M, Adriaensen D, Cichocki T (2000) Development of the innervation of long bones: expression of the growth-associated protein 43. Folia Histochem Cytobiol 38:103–110
Gajda M, Litwin JA, Tabarowski Z, Zagolski O, Cichocki T, Timmermans JP, Adriaensen D (2010) Development of rat tibia innervation: colocalization of autonomic nerve fiber markers with growth-associated protein 43. Cells Tissues Organs 191:489–499
Sisask G, Bjurholm A, Ahmed M, Kreicbergs A (1995) Ontogeny of sensory nerves in the developing skeleton. Anat Rec 243:234–240
Sisask G, Bjurholm A, Ahmed M, Kreicbergs A (1996) The development of autonomic innervation in bone and joints of the rat. J Auton Nerv Syst 59:27–33
Martini R, Schachner M (1991) Complex expression pattern of tenascin during innervation of the posterior limb buds of the developing chicken. J Neurosci Res 28:261–279
Gomez C, Burt-Pichat B, Mallein-Gerin F, Merle B, Delmas PD, Skerry TM, Vico L, Malaval L, Chenu C (2005) Expression of Semaphorin-3A and its receptors in endochondral ossification: potential role in skeletal development and innervation. Dev Dyn 234:393–403
Guha U, Gomes WA, Samanta J, Gupta M, Rice FL, Kessler JA (2004) Target-derived BMP signaling limits sensory neuron number and the extent of peripheral innervation in vivo. Development 131:1175–1186
Gray C, Hukkanen M, Konttinen YT, Terenghi G, Arnett TR, Jones SJ, Burnstock G, Polak JM (1992) Rapid neural growth: calcitonin gene-related peptide and substance P-containing nerves attain exceptional growth rates in regenerating deer antler. Neuroscience 50:953–963
Singh IJ, Herskovits MS, Chiego DJ Jr, Klein RM (1982) Modulation of osteoblastic activity by sensory and autonomic innervation of bone. Prog Clin Biol Res 101:535–551
Suttie JM, Fennessy PF (1985) Regrowth of amputated velvet antlers with and without innervation. J Exp Zool 234:359–366
Hukkanen M, Konttinen YT, Santavirta S, Paavolainen P, Gu XH, Terenghi G, Polak JM (1993) Rapid proliferation of calcitonin gene-related peptide-immunoreactive nerves during healing of rat tibial fracture suggests neural involvement in bone growth and remodelling. Neuroscience 54:969–979
Strange-Vognsen HH, Laursen H (1997) Nerves in human epiphyseal uncalcified cartilage. J Pediatr Orthop B 6:56–58
Li J, Ahmad T, Spetea M, Ahmed M, Kreicbergs A (2001) Bone reinnervation after fracture: a study in the rat. J Bone Miner Res 16:1505–1510
Tam J, Trembovler V, Di Marzo V, Petrosino S, Leo G, Alexandrovich A, Regev E, Casap N, Shteyer A, Ledent C, Karsak M, Zimmer A, Mechoulam R, Yirmiya R, Shohami E, Bab I (2008) The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling. FASEB J 22:285–294
Edoff K, Grenegard M, Hildebrand C (2000) Retrograde tracing and neuropeptide immunohistochemistry of sensory neurones projecting to the cartilaginous distal femoral epiphysis of young rats. Cell Tissue Res 299:193–200
Maassen AP (1952) The influence of adrenalectomy on the growth of rats. Arch Int Pharmacodyn Ther 88:473–481
Paul MI, Kvetnansky R, Cramer H, Silbergeld S, Kopin IJ (1971) Immobilization stress induced changes in adrenocortical and medullary cyclic AMP content in the rat. Endocrinology 88:338–344
Smith DM, Johnston CC Jr (1974) Hormonal responsiveness of adenylate cyclase activity from separate bone cells. Endocrinology 95:130–139
Wong GL (1979) Induction of metabolic changes and down regulation of bovine parathyroid hormone-responsive adenylate cyclase are dissociable in isolated osteoclastic and osteoblastic bone cells. J Biol Chem 254:34–37
Lipski S (1976) Effects of beta-adrenergic stimulation on bone-marrow function in normal and sublethally irradiated mice. I. The effect of isoproterenol on cAMP content in bone-marrow cells in vivo and in vitro. Int J Radiat Biol Relat Stud Phys Chem Med 29:359–366
Gutierrez GE, Mundy GR, Katz MS (1984) Adenylate cyclase of osteoblast-like cells from rat osteosarcoma is stimulated by calcitonin as well as parathyroid hormone. Endocrinology 115:2342–2346
Moore RE, Smith CK II, Bailey CS, Voelkel EF, Tashjian AH Jr (1993) Characterization of beta-adrenergic receptors on rat and human osteoblast-like cells and demonstration that beta-receptor agonists can stimulate bone resorption in organ culture. Bone Miner 23:301–315
Togari A, Arai M, Mizutani S, Mizutani S, Koshihara Y, Nagatsu T (1997) Expression of mRNAs for neuropeptide receptors and beta-adrenergic receptors in human osteoblasts and human osteogenic sarcoma cells. Neurosci Lett 233:125–128
Kellenberger S, Muller K, Richener H, Bilbe G (1998) Formoterol and isoproterenol induce c-fos gene expression in osteoblast-like cells by activating beta2-adrenergic receptors. Bone 22:471–478
Majeska RJ, Minkowitz B, Bastian W, Einhorn TA (1992) Effects of beta-adrenergic blockade in an osteoblast-like cell line. J Orthop Res 10:379–384
Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G (2005) Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434:514–520
Aitken SJ, Landao-Bassonga E, Ralston SH, Idris AI (2009) Beta2-adrenoreceptor ligands regulate osteoclast differentiation in vitro by direct and indirect mechanisms. Arch Biochem Biophys 482:96–103
Kondo H, Takeuchi S, Togari A (2013) Beta-adrenergic signaling stimulates osteoclastogenesis via reactive oxygen species. Am J Physiol Endocrinol Metab 304:E507–E515
Takahata Y, Takarada T, Iemata M, Yamamoto T, Nakamura Y, Kodama A, Yoneda Y (2009) Functional expression of beta2 adrenergic receptors responsible for protection against oxidative stress through promotion of glutathione synthesis after Nrf2 upregulation in undifferentiated mesenchymal C3H10T1/2 stem cells. J Cell Physiol 218:268–275
Lai LP, Mitchell J (2008) Beta2-adrenergic receptors expressed on murine chondrocytes stimulate cellular growth and inhibit the expression of Indian hedgehog and collagen type X. J Cell Biochem 104:545–553
Fonseca TL, Jorgetti V, Costa CC, Capelo LP, Covarrubias AE, Moulatlet AC, Teixeira MB, Hesse E, Morethson P, Beber EH, Freitas FR, Wang CC, Nonaka KO, Oliveira R, Casarini DE, Zorn TM, Brum PC, Gouveia CH (2011) Double disruption of alpha2A- and alpha2C-adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype. J Bone Miner Res 26:591–603
Mitchell J, Lai LP, Peralta F, Xu Y, Sugamori K (2011) Beta2-adrenergic receptors inhibit the expression of collagen type II in growth plate chondrocytes by stimulating the AP-1 factor Jun-B. Am J Physiol Endocrinol Metab 300:E633–E639
Vignon E, Broquet P, Mathieu P, Louisot P, Richard M (1990) Histaminergic H1, serotoninergic, beta adrenergic and dopaminergic receptors in human osteoarthritic cartilage. Biochem Int 20:251–255
Kitaura T, Tsunekawa N, Kraemer WJ (2002) Inhibited longitudinal growth of bones in young male rats by clenbuterol. Med Sci Sports Exerc 34:267–273
Whitsett JA, Burdsall J, Workman L, Hollinger B, Neely J (1983) Beta-adrenergic receptors in pediatric tumors: uncoupled beta 1-adrenergic receptor in Ewing’s sarcoma. J Natl Cancer Inst 71:779–786
Nuntapornsak A, Wongdee K, Thongbunchoo J, Krishnamra N, Charoenphandhu N (2010) Changes in the mRNA expression of osteoblast-related genes in response to beta(3)-adrenergic agonist in UMR106 cells. Cell Biochem Funct 28:45–51
Hsiao EC, Boudignon BM, Chang WC, Bencsik M, Peng J, Nguyen TD, Manalac C, Halloran BP, Conklin BR, Nissenson RA (2008) Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass. Proc Natl Acad Sci USA 105:1209–1214
Park H, No AL, Lee JM, Chen L, Lee SY, Lee DS, Yim M (2010) PDE4 inhibitor upregulates PTH-induced osteoclast formation via CRE-mediated COX-2 expression in osteoblasts. FEBS Lett 584:173–180
Cho ES, Yu JH, Kim MS, Yim M (2004) Rolipram, a phosphodiesterase 4 inhibitor, stimulates osteoclast formation by inducing TRANCE expression in mouse calvarial cells. Arch Pharmacol Res 27:1258–1262
Kinoshita T, Kobayashi S, Ebara S, Yoshimura Y, Horiuchi H, Tsutsumimoto T, Wakabayashi S, Takaoka K (2000) Phosphodiesterase inhibitors, pentoxifylline and rolipram, increase bone mass mainly by promoting bone formation in normal mice. Bone 27:811–817
Takami M, Cho ES, Lee SY, Kamijo R, Yim M (2005) Phosphodiesterase inhibitors stimulate osteoclast formation via TRANCE/RANKL expression in osteoblasts: possible involvement of ERK and p38 MAPK pathways. FEBS Lett 579:832–838
Hausdorff WP, Lohse MJ, Bouvier M, Liggett SB, Caron MG, Lefkowitz RJ (1990) Two kinases mediate agonist-dependent phosphorylation and desensitization of the beta 2-adrenergic receptor. Symp Soc Exp Biol 44:225–240
Lin FT, Daaka Y, Lefkowitz RJ (1998) Beta-arrestins regulate mitogenic signaling and clathrin-mediated endocytosis of the insulin-like growth factor I receptor. J Biol Chem 273:31640–31643
Bliziotes M, Gunness M, Zhang X, Nissenson R, Wiren K (2000) Reduced G-protein-coupled-receptor kinase 2 activity results in impairment of osteoblast function. Bone 27:367–373
Bliziotes M, Murtagh J, Wiren K (1996) Beta-adrenergic receptor kinase-like activity and beta-arrestin are expressed in osteoblastic cells. J Bone Miner Res 11:820–826
Spurney RF, Flannery PJ, Garner SC, Athirakul K, Liu S, Guilak F, Quarles LD (2002) Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts. J Clin Investig 109:1361–1371
Wang L, Liu S, Quarles LD, Spurney RF (2005) Targeted overexpression of G protein-coupled receptor kinase-2 in osteoblasts promotes bone loss. Am J Physiol Endocrinol Metab 288:E826–E834
Bonnet N, Benhamou CL, Brunet-Imbault B, Arlettaz A, Horcajada MN, Richard O, Vico L, Collomp K, Courteix D (2005) Severe bone alterations under beta2 agonist treatments: bone mass, microarchitecture and strength analyses in female rats. Bone 37:622–633
Bonnet N, Benhamou CL, Beaupied H, Laroche N, Vico L, Dolleans E, Courteix D (2007) Doping dose of salbutamol and exercise: deleterious effect on cancellous and cortical bones in adult rats. J Appl Physiol 102:1502–1509
Kondo A, Mogi M, Koshihara Y, Togari A (2001) Signal transduction system for interleukin-6 and interleukin-11 synthesis stimulated by epinephrine in human osteoblasts and human osteogenic sarcoma cells. Biochem Pharmacol 61:319–326
Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17:1231–1234
Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA (2011) Matrix-embedded cells control osteoclast formation. Nat Med 17:1235–1241
Fu L, Patel MS, Bradley A, Wagner EF, Karsenty G (2005) The molecular clock mediates leptin-regulated bone formation. Cell 122:803–815
Bonnet N, Benhamou CL, Malaval L, Goncalves C, Vico L, Eder V, Pichon C, Courteix D (2008) Low dose beta-blocker prevents ovariectomy-induced bone loss in rats without affecting heart functions. J Cell Physiol 217:819–827
Kajimura D, Hinoi E, Ferron M, Kode A, Riley KJ, Zhou B, Guo XE, Karsenty G (2011) Genetic determination of the cellular basis of the sympathetic regulation of bone mass accrual. J Exp Med 208:841–851
Bonnet N, Pierroz DD, Ferrari SL (2008) Adrenergic control of bone remodeling and its implications for the treatment of osteoporosis. J Musculoskelet Neuron Interact 8:94–104
Pierroz DD, Bonnet N, Bianchi EN, Bouxsein ML, Baldock PA, Rizzoli R, Ferrari SL (2012) Deletion of beta-adrenergic receptor 1, 2, or both leads to different bone phenotypes and response to mechanical stimulation. J Bone Miner Res 27:1252–1262
Swift JM, Hogan HA, Bloomfield SA (2013) Beta-1 adrenergic agonist mitigates unloading-induced bone loss by maintaining formation. Med Sci Sports Exerc. doi:10.1249/MSS.0b013e31828d39bc
Bouxsein ML, Devlin MJ, Glatt V, Dhillon H, Pierroz DD, Ferrari SL (2009) Mice lacking beta-adrenergic receptors have increased bone mass but are not protected from deleterious skeletal effects of ovariectomy. Endocrinology 150:144–152
Motyl KJ, Bishop KA, Demambro VE, Bornstein SA, Le P, Kawai M, Lotinun S, Horowitz MC, Baron R, Bouxsein ML, Rosen CJ (2013) Altered thermogenesis and impaired bone remodeling in Misty mice. J Bone Miner Res. doi:10.1002/jbmr.1943
Bonnet N, Laroche N, Vico L, Dolleans E, Benhamou CL, Courteix D (2006) Dose effects of propranolol on cancellous and cortical bone in ovariectomized adult rats. J Pharmacol Exp Ther 318:1118–1127
Kondo H, Nifuji A, Takeda S, Ezura Y, Rittling SR, Denhardt DT, Nakashima K, Karsenty G, Noda M (2005) Unloading induces osteoblastic cell suppression and osteoclastic cell activation to lead to bone loss via sympathetic nervous system. J Biol Chem 280:30192–30200
Sato T, Arai M, Goto S, Togari A (2010) Effects of propranolol on bone metabolism in spontaneously hypertensive rats. J Pharmacol Exp Ther 334:99–105
Wang TM, Hsu JF, Jee WS, Matthews JL (1993) Evidence for reduced cancellous bone mass in the spontaneously hypertensive rat. Bone Miner 20:251–264
Gotoh M, Mizuno K, Ono Y, Takahashi M (2005) High blood pressure, bone-mineral loss and insulin resistance in women. Hypertens Res 28:565–570
Young E, Korszun A (2009) Stress, the HPA axis and depressive illness. In: Larry RS (ed) Encyclopedia of neuroscience. Academic Press, Oxford, pp 543–548
Lindenfeld J, Crawford MH, O’Rourke RA, Levine SP, Montiel MM, Horwitz LD (1980) Adrenergic responsiveness after abrupt propranolol withdrawal in normal subjects and in patients with angina pectoris. Circulation 62:704–711
Boudoulas H, Lewis RP, Kates RE, Dalamangas G (1977) Hypersensitivity to adrenergic stimulation after propranolol withdrawal in normal subjects. Ann Intern Med 87:433–436
Granata AR (1985) Prolonged treatment with (+/−) propranolol induces supersensitivity to (l)noradrenaline in mesenteric arteries in the rat. Gen Pharmacol 16:463–468
Karliner JS (1989) Effects of beta-blockade on beta-adrenergic receptors and signal transduction. J Cardiovasc Pharmacol 14(Suppl 5):S6–S12
Tse J, Wrenn RW, Kuo JF (1980) Thyroxine-induced changes in characteristics and activities of beta-adrenergic receptors and adenosine 3′,5′-monophosphate and guanosine 3′,5′-monophosphate systems in the heart may be related to reputed catecholamine supersensitivity in hyperthyroidism. Endocrinology 107:6–16
Aarons RD, Nies AS, Gal J, Hegstrand LR, Molinoff PB (1980) Elevation of beta-adrenergic receptor density in human lymphocytes after propranolol administration. J Clin Investig 65:949–957
Ma Y, Nyman JS, Tao H, Moss HH, Yang X, Elefteriou F (2011) Beta2-adrenergic receptor signaling in osteoblasts contributes to the catabolic effect of glucocorticoids on bone. Endocrinology 152:1412–1422
Robbins J, Hirsch C, Whitmer R, Cauley J, Harris T (2001) The association of bone mineral density and depression in an older population. J Am Geriatr Soc 49:732–736
Cizza G, Primma S, Csako G (2009) Depression as a risk factor for osteoporosis. Trends Endocrinol Metab 20:367–373
Michelson D, Stratakis C, Hill L, Reynolds J, Galliven E, Chrousos G, Gold P (1996) Bone mineral density in women with depression. N Engl J Med 335:1176–1181
Yazici KM, Akinci A, Sutcu A, Ozcakar L (2003) Bone mineral density in premenopausal women with major depressive disorder. Psychiatry Res 117:271–275
Kahl KG, Rudolf S, Stoeckelhuber BM, Dibbelt L, Gehl HB, Markhof K, Hohagen F, Schweiger U (2005) Bone mineral density, markers of bone turnover, and cytokines in young women with borderline personality disorder with and without comorbid major depressive disorder. Am J Psychiatry 162:168–174
Ensrud KE, Blackwell T, Mangione CM, Bowman PJ, Bauer DC, Schwartz A, Hanlon JT, Nevitt MC, Whooley MA, Study of Osteoporotic Fractures Research G (2003) Central nervous system active medications and risk for fractures in older women. Arch Intern Med 163:949–957
Esler M, Rumantir M, Wiesner G, Kaye D, Hastings J, Lambert G (2001) Sympathetic nervous system and insulin resistance: from obesity to diabetes. Am J Hypertens 14:304S–309S
Lutgendorf SK, DeGeest K, Dahmoush L, Farley D, Penedo F, Bender D, Goodheart M, Buekers TE, Mendez L, Krueger G, Clevenger L, Lubaroff DM, Sood AK, Cole SW (2011) Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun 25:250–255
Hughes JW, Watkins L, Blumenthal JA, Kuhn C, Sherwood A (2004) Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. J Psychosom Res 57:353–358
Yirmiya R, Goshen I, Bajayo A, Kreisel T, Feldman S, Tam J, Trembovler V, Csernus V, Shohami E, Bab I (2006) Depression induces bone loss through stimulation of the sympathetic nervous system. Proc Natl Acad Sci USA 103:16876–16881
Campbell JP, Karolak MR, Ma Y, Perrien DS, Masood-Campbell SK, Penner NL, Munoz SA, Zijlstra A, Yang X, Sterling JA, Elefteriou F (2012) Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. PLoS Biol 10:e1001363
Powe DG, Voss MJ, Zanker KS, Habashy HO, Green AR, Ellis IO, Entschladen F (2010) Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 1:628–638
Ganz PA, Habel LA, Weltzien EK, Caan BJ, Cole SW (2011) Examining the influence of beta blockers and ACE inhibitors on the risk for breast cancer recurrence: results from the LACE cohort. Breast Cancer Res Treat 129:549–556
Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, Sood AK, Conzen SD, Hortobagyi GN, Gonzalez-Angulo AM (2011) Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol 29:2645–2652
Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K (2011) Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol 29:2635–2644
Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Myers MG Jr, Chua SC Jr, Kim JK, Kaestner KH, Karsenty G (2008) The sympathetic tone mediates leptin’s inhibition of insulin secretion by modulating osteocalcin bioactivity. J Cell Biol 183:1235–1242
Altman JD, Trendelenburg AU, MacMillan L, Bernstein D, Limbird L, Starke K, Kobilka BK, Hein L (1999) Abnormal regulation of the sympathetic nervous system in alpha2A-adrenergic receptor knockout mice. Mol Pharmacol 56:154–161
Han J, Zou Z, Zhu C, Deng J, Wang J, Ran X, Shi C, Ai G, Li R, Cheng T, Su Y (2009) DNA synthesis of rat bone marrow mesenchymal stem cells through alpha1-adrenergic receptors. Arch Biochem Biophys 490:96–102
Nishiura T, Abe K (2007) Alpha1-adrenergic receptor stimulation induces the expression of receptor activator of nuclear factor kappaB ligand gene via protein kinase C and extracellular signal-regulated kinase pathways in MC3T3-E1 osteoblast-like cells. Arch Oral Biol 52:778–785
Huang HH, Brennan TC, Muir MM, Mason RS (2009) Functional alpha1- and beta2-adrenergic receptors in human osteoblasts. J Cell Physiol 220:267–275
Choi YJ, Lee JY, Lee SJ, Chung CP, Park YJ (2011) Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation. Biochem Biophys Res Commun 416:232–238
Idris AI, van ‘t Hof RJ, Greig IR, Ridge SA, Baker D, Ross RA, Ralston SH (2005) Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med 11:774–779
Tam J, Ofek O, Fride E, Ledent C, Gabet Y, Muller R, Zimmer A, Mackie K, Mechoulam R, Shohami E, Bab I (2006) Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling. Mol Pharmacol 70:786–792
Wong PK, Christie JJ, Wark JD (2007) The effects of smoking on bone health. Clin Sci 113:233–241
Walker LM, Preston MR, Magnay JL, Thomas PB, El Haj AJ (2001) Nicotinic regulation of c-fos and osteopontin expression in human-derived osteoblast-like cells and human trabecular bone organ culture. Bone 28:603–608
Rothem DE, Rothem L, Soudry M, Dahan A, Eliakim R (2009) Nicotine modulates bone metabolism-associated gene expression in osteoblast cells. J Bone Miner Metab 27:555–561
Bajayo A, Bar A, Denes A, Bachar M, Kram V, Attar-Namdar M, Zallone A, Kovacs KJ, Yirmiya R, Bab I (2012) Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual. Proc Natl Acad Sci USA 109:15455–15460
Shi Y, Oury F, Yadav VK, Wess J, Liu XS, Guo XE, Murshed M, Karsenty G (2010) Signaling through the M(3) muscarinic receptor favors bone mass accrual by decreasing sympathetic activity. Cell Metab 11:231–238
Reid IR, Gamble GD, Grey AB, Black DM, Ensrud KE, Browner WS, Bauer DC (2005) Beta-blocker use, BMD, and fractures in the study of osteoporotic fractures. J Bone Miner Res 20:613–618
Rejnmark L, Vestergaard P, Kassem M, Christoffersen BR, Kolthoff N, Brixen K, Mosekilde L (2004) Fracture risk in perimenopausal women treated with beta-blockers. Calcif Tissue Int 75:365–372
Graham S, Hammond-Jones D, Gamie Z, Polyzois I, Tsiridis E, Tsiridis E (2008) The effect of beta-blockers on bone metabolism as potential drugs under investigation for osteoporosis and fracture healing. Expert Opin Investig Drugs 17:1281–1299
Reid IR (2008) Effects of beta-blockers on fracture risk. J Musculoskelet Neuron Interact 8:105–110
Bonnet N, Gadois C, McCloskey E, Lemineur G, Lespessailles E, Courteix D, Benhamou CL (2007) Protective effect of beta blockers in postmenopausal women: influence on fractures, bone density, micro and macroarchitecture. Bone 40:1209–1216
Reid IR, Lucas J, Wattie D, Horne A, Bolland M, Gamble GD, Davidson JS, Grey AB (2005) Effects of a beta-blocker on bone turnover in normal postmenopausal women: a randomized controlled trial. J Clin Endocrinol Metab 90:5212–5216
Levasseur R, Legrand E, Chappard D, Audran M (2005) Central control of bone mass: potential therapeutic implications. Jt Bone Spine 72:474–476
Goldstein DS, Holmes C, Sharabi Y, Brentzel S, Eisenhofer G (2003) Plasma levels of catechols and metanephrines in neurogenic orthostatic hypotension. Neurology 60:1327–1332
Robertson D, Haile V, Perry SE, Robertson RM, Phillips JA III, Biaggioni I (1991) Dopamine beta-hydroxylase deficiency. A genetic disorder of cardiovascular regulation. Hypertension 18:1–8
Biaggioni I, Robertson D (1987) Endogenous restoration of noradrenaline by precursor therapy in dopamine-beta-hydroxylase deficiency. Lancet 2:1170–1172
Man in ‘t Veld AJ, Boomsma F, Moleman P, Schalekamp MA (1987) Congenital dopamine-beta-hydroxylase deficiency. A novel orthostatic syndrome. Lancet 1:183–188
Tinetti ME, Speechley M, Ginter SF (1988) Risk factors for falls among elderly persons living in the community. N Engl J Med 319:1701–1707
Graafmans WC, Ooms ME, Hofstee HM, Bezemer PD, Bouter LM, Lips P (1996) Falls in the elderly: a prospective study of risk factors and risk profiles. Am J Epidemiol 143:1129–1136
Robertson D (1999) The epidemic of orthostatic tachycardia and orthostatic intolerance. Am J Med Sci 317:75–77
Low PA, Opfer-Gehrking TL, Textor SC, Benarroch EE, Shen WK, Schondorf R, Suarez GA, Rummans TA (1995) Postural tachycardia syndrome (POTS). Neurology 45:S19–S25
Benarroch EE (2012) Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc 87:1214–1225
de Vries F, Pouwels S, Bracke M, Leufkens HG, Cooper C, Lammers JW, van Staa TP (2007) Use of beta-2 agonists and risk of hip/femur fracture: a population-based case-control study. Pharmacoepidemiol Drug Saf 16:612–619
Veldhuis-Vlug AG, El Mahdiui M, Endert E, Heijboer AC, Fliers E, Bisschop PH (2012) Bone resorption is increased in pheochromocytoma patients and normalizes following adrenalectomy. J Clin Endocrinol Metab 97:E2093–E2097
Kado DM, Lui LY, Cummings SR, Study of Osteoporotic Fractures Research Group (2002) Rapid resting heart rate: a simple and powerful predictor of osteoporotic fractures and mortality in older women. J Am Geriatr Soc 50:455–460
Tosun A, Dogru MT, Aydn G, Keles I, Arslan A, Guneri M, Orkun S, Ebinc H (2011) Does autonomic dysfunction exist in postmenopausal osteoporosis? Am J Phys Med Rehabil 90:1012–1019
Farr JN, Charkoudian N, Barnes JN, Monroe DG, McCready LK, Atkinson EJ, Amin S, Melton LJ III, Joyner MJ, Khosla S (2012) Relationship of sympathetic activity to bone microstructure, turnover, and plasma osteopontin levels in women. J Clin Endocrinol Metab 97:4219–4227
Author information
Authors and Affiliations
Corresponding author
Additional information
The authors report that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Elefteriou, F., Campbell, P. & Ma, Y. Control of Bone Remodeling by the Peripheral Sympathetic Nervous System. Calcif Tissue Int 94, 140–151 (2014). https://doi.org/10.1007/s00223-013-9752-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00223-013-9752-4