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NPY and bone

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NPY Family of Peptides in Neurobiology, Cardiovascular and Metabolic Disorders: from Genes to Therapeutics

Part of the book series: Experientia Supplementum ((EXS,volume 95))

Concluding remarks

Genetic models such as Y receptor knockout and leptin knockout mice have begun to reveal some of the individual functions of the different Y receptors. The finding that some of these receptors appear to be involved in the regulation of bone formation via a hypothalamic relay, has revealed not only a previously unknown and novel function of the Y receptors, but also a novel example of the regulation of bone formation by a very potent, centrally-mediated mechanism.

The rapid increase in bone mass in adult mice following central deletion of Y2 receptor function suggests new possibilities for the prevention and anabolic treatment of osteoporosis. The Y2 receptor pathway appears to be distinct from the antiosteogenic pathway regulated by leptin, and therefore supports the Y2 regulated pathway as a novel target for anabolic bone therapy. Furthermore, the area of the arcuate nucleus where the Y2 receptors are located is accessible without the need to cross the blood brain barrier, and is therefore potentially an ideal target for drug intervention. The additional advantage of this particular sub-population of arcuate Y2 receptors is that their specific inhibition will not influence any other central functions of the Y2 receptor such as effects on seizure susceptibility, anxiety, or memory, therefore limiting the possibility of side effects associated with such a treatment for osteoporosis.

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References

  1. Baldock PA, Sainsbury A, Couzens M, Enriquez RF, Thomas GP, Gardiner EM, Herzog H (2002) Hypothalamic Y2 receptors regulate bone formation. J Clin Invest 109: 915–921

    Article  CAS  PubMed  Google Scholar 

  2. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100: 197–207

    Article  CAS  PubMed  Google Scholar 

  3. Vaananen HK, Harkonen PL (1996) Estrogen and bone metabolism. Maturitas 23Suppl: S65–69

    CAS  PubMed  Google Scholar 

  4. Marie P (1997) Growth factors and bone formation in osteoporosis: roles for IGF-I and TGF-beta. Rev Rhum Engl Ed 64: 44–53

    CAS  PubMed  Google Scholar 

  5. de Vernejoul MC (1996) Dynamics of bone remodelling: biochemical and pathophysiological basis. Eur J Clin Chem Clin Biochem 34: 729–734

    PubMed  Google Scholar 

  6. Cooper C, Melton III LJ (1996) Magnitude and impact of osteoporosis and fractures. In: R Marcus, D Feldman, J Kelsey (eds): Osteoporosis. Academic Press, San Diego, 419–434

    Google Scholar 

  7. Baron R, Ravesloot JH, Neff L, Chakraborty M, Chatterjee D, Lombri A, Horne W (1993) Cellular and molecular biology of the osteoclast. In: M Noda (ed.): Cellular and molecular biology of bone. Academic Press, San Diego, 445–495

    Google Scholar 

  8. Bjurholm A, Kreicbergs A, Brodin E, Schultzberg M (1988) Substance P-and CGRP-immunoreactive nerves in bone. Peptides 9: 165–171

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Hukkanen M, Konttinen YT, Rees RG, Santavirta S, Terenghi G, Polak JM (1992) Distribution of nerve endings and sensory neuropeptides in rat synovium, meniscus and bone. Int J Tissue React 14: 1–10

    CAS  PubMed  Google Scholar 

  12. Tabarowski Z, Gibson-Berry K, Felten SY (1996) Noradrenergic and peptidergic innervation of the mouse femur bone marrow. Acta Histochem 98: 453–457

    CAS  PubMed  Google Scholar 

  13. Bjurholm A (1991) Neuroendocrine peptides in bone. Int Orthop 15: 325–329

    Article  CAS  PubMed  Google Scholar 

  14. Lundberg P, Lerner UH (2002) Expression and regulatory role of receptors for vasoactive intestinal peptide in bone cells. Microsc Res Tech 58: 98–103

    Article  CAS  PubMed  Google Scholar 

  15. Michelangeli VP, Fletcher AE, Allan EH, Nicholson GC, Martin TJ (1989) Effects of calcitonin gene-related peptide on cyclic AMP formation in chicken, rat, and mouse bone cells. J Bone Miner Res 4: 269–272

    CAS  PubMed  Google Scholar 

  16. Thiebaud D, Akatsu T, Yamashita T, Suda T, Noda T, Martin RE, Fletcher AE, Martin TJ (1991) Structure-activity relationships in calcitonin gene-related peptide: cyclic AMP response in a preosteoblast cell line (KS-4). J Bone Miner Res 6: 1137–1142

    CAS  PubMed  Google Scholar 

  17. Bjurholm A, Kreicbergs A, Schultzberg M, Lerner UH (1992) Neuroendocrine regulation of cyclic AMP formation in osteoblastic cell lines (UMR-106-01, ROS 17/2.8, MC3T3-E1, and Saos-2) and primary bone cells. J Bone Miner Res 7: 1011–1019

    CAS  PubMed  Google Scholar 

  18. Shih C, Bernard GW (1997) Calcitonin gene related peptide enhances bone colony development in vitro. Clin Orthop 334: 335–344

    PubMed  Google Scholar 

  19. Ballica R, Valentijn K, Khachatryan A, Guerder S, Kapadia S, Gundberg C, Gilligan J, Flavell RA, Vignery A (1999) Targeted expression of calcitonin gene-related peptide to osteoblasts increases bone density in mice. J Bone Miner Res 14: 1067–1074

    CAS  PubMed  Google Scholar 

  20. Goto T, Yamaza T, Kido MA, Tanaka T (1998) Light-and electron-microscopic study of the distribution of axons containing substance P and the localization of neurokinin-1 receptor in bone. Cell Tissue Res 293: 87–93

    Article  CAS  PubMed  Google Scholar 

  21. Lundberg P, Bostrom I, Mukohyama H, Bjurholm A, Smans K, Lerner UH (1999) Neuro-hormonal control of bone metabolism: vasoactive intestinal peptide stimulates alkaline phosphatase activity and mRNA expression in mouse calvarial osteoblasts as well as calcium accumulation mineralized bone nodules. Regul Pept 85: 47–58

    Article  CAS  PubMed  Google Scholar 

  22. Mori T, Ogata T, Okumura H, Shibata T, Nakamura Y, Kataoka K (1999) Substance P regulates the function of rabbit cultured osteoclast; increase of intracellular free calcium concentration and enhancement of bone resorption. Biochem Biophys Res Commun 262: 418–422

    Article  CAS  PubMed  Google Scholar 

  23. Mason DJ, Suva LJ, Genever PG, Patton AJ, Steuckle S, Hillam RA, Skerry TM (1997) Mechanically regulated expression of a neural glutamate transporter in bone: a role for excitatory amino acids as osteotropic agents? Bone 20: 199–205

    Article  CAS  PubMed  Google Scholar 

  24. Chenu C, Serre CM, Raynal C, Burt-Pichat B, Delmas PD (1998) Glutamate receptors are expressed by bone cells and are involved in bone resorption. Bone 22: 295–299

    Article  CAS  PubMed  Google Scholar 

  25. Peet NM, Grabowski PS, Laketic-Ljubojevic I, Skerry TM (1999) The glutamate receptor antagonist MK801 modulates bone resorption in vitro by a mechanism predominantly involving osteoclast differentiation. FASEB J 13: 2179–2185

    CAS  PubMed  Google Scholar 

  26. Bliziotes MM, Eshleman AJ, Zhang XW, Wiren KM (2001) Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone 29: 477–486

    Article  CAS  PubMed  Google Scholar 

  27. Westbroek I, van der Plas A, de Rooij KE, Klein-Nulend J, Nijweide PJ (2001) Expression of serotonin receptors in bone. J Biol Chem 276: 28961–28968

    Article  CAS  PubMed  Google Scholar 

  28. Larhammar D, Blomqvist AG, Yee F, Jazin E, Yoo H, Wahlested C (1992) Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type. J Biol Chem 267: 10935–10938

    CAS  PubMed  Google Scholar 

  29. Gerald C, Walker MW, Criscione L, Gustafson EL, Batzl-Hartmann C, Smith KE, Vaysse P, Durkin MM, Laz TM, Linemeyer DL et al. (1996) A receptor subtype involved in neuropeptide-Yinduced food intake. Nature 382: 168–171

    Article  CAS  PubMed  Google Scholar 

  30. Blomqvist AG, Herzog H (1997) Y-receptor subtypes — how many more? Trends Neurosci 20: 294–298

    Article  CAS  PubMed  Google Scholar 

  31. Naveilhan P, Neveu I, Arenas E, Ernfors P (1998) Complementary and overlapping expression of Y1, Y2 and Y5 receptors in the developing and adult mouse nervous system. Neuroscience 87: 289–302

    Article  CAS  PubMed  Google Scholar 

  32. Parker RM, Herzog H (1999) Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur J Neurosci 1999 11: 1431–1448

    CAS  PubMed  Google Scholar 

  33. Mullins DE, Guzzi M, Xia L, Parker EM (2000) Pharmacological characterization of the cloned neuropeptide Y y(6) receptor. Eur J Pharmacol 395: 87–93

    Article  CAS  PubMed  Google Scholar 

  34. Sainsbury A, Baldock PA, Schwarzer C, Ueno N, Enriquez RF, Couzens M, Inui A, Herzog H, Gardiner EM (2003) Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice. Mol Cell Biol 23: 5225–5233

    Article  CAS  PubMed  Google Scholar 

  35. Tremollieres FA, Pouilles JM, Ribot C (1993) Vertebral postmenopausal bone loss is reduced in overweight women: a longitudinal study in 155 early postmenopausal women. J Clin Endocrinol Metab 77: 683–686

    Article  CAS  PubMed  Google Scholar 

  36. Albala C, Yanez M, Devoto E, Sostin C, Zeballos L, Santos JL (1996) Obesity as a protective factor for postmenopausal osteoporosis. Int J Obes Relat Metab Disord 20: 1027–1032

    CAS  PubMed  Google Scholar 

  37. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395: 763–770

    Article  CAS  PubMed  Google Scholar 

  38. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J et al. (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83: 1263–1271

    Article  CAS  PubMed  Google Scholar 

  39. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A et al. (1995) The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377: 530–532

    Article  CAS  PubMed  Google Scholar 

  40. Coleman DL (1988) Classical diabetes models: past lessons and potential new therapies. In: E Shafrir, AE Renold (eds): Frontiers in diabetes research. Lessons from animal diabetes II. John Libbey and Co Ltd, London, 253–256

    Google Scholar 

  41. Erickson JC, Hollopeter G, Palmiter RD (1996) Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274: 1704–1707

    Article  CAS  PubMed  Google Scholar 

  42. Cornish J, Callon KE, Bava U, Lin C, Naot D, Hill BL, Grey AB, Broom N, Myers DE, Nicholson GC et al. (2002) Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo. J Endocrinol 175: 405–415

    Article  CAS  PubMed  Google Scholar 

  43. Steppan CM, Crawford DT, Chidsey-Frink KL, Ke H, Swick AG (2000) Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept 92: 73–78

    Article  CAS  PubMed  Google Scholar 

  44. Reseland JE, Syversen U, Bakke I, Qvigstad G, Eide LG, Hjertner O, Gordeladze JO, Drevon CA (2001) Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization. J Bone Miner Res 16: 1426–1433

    CAS  PubMed  Google Scholar 

  45. 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

    Article  CAS  PubMed  Google Scholar 

  46. Broadwell RD, Brightman MW (1976) Entry of peroxidase into neurons of the central and peripheral nervous systems from extracerebral and cerebral blood. J Comp Neurol 166: 257–283

    Article  CAS  PubMed  Google Scholar 

  47. Baskin DG, Breininger JF, Schwartz MW (1999) Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. Diabetes 48: 828–833

    CAS  PubMed  Google Scholar 

  48. Inui A (1999) Feeding and body-weight regulation by hypothalamic neuropeptides — mediation of the actions of leptin. Trends Neurosci 22: 62–67

    Article  CAS  PubMed  Google Scholar 

  49. Broberger C, Landry M, Wong H, Walsh JN, Hokfelt T (1997) Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin-and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 66: 393–408

    CAS  PubMed  Google Scholar 

  50. King PJ, Williams G, Doods H, Widdowson PS (2000) Effect of a selective neuropeptide Y Y(2) receptor antagonist, BIIE0246 on neuropeptide Y release. Eur J Pharmacol 396: R1–3

    Article  CAS  PubMed  Google Scholar 

  51. Sainsbury A, Schwarzer C, Couzens M, Herzog H (2002) Y2 receptor deletion attenuates the type 2 diabetic syndrome of ob/ob mice. Diabetes 51: 3420–3427

    CAS  PubMed  Google Scholar 

  52. Naveilhan P, Svensson L, Nystrom S, Ekstrand AJ, Ernfors P (2002) Attenuation of hypercholesterolemia and hyperglycemia in ob/ob mice by NPY Y2 receptor ablation. Peptides 23: 1087–1091

    Article  CAS  PubMed  Google Scholar 

  53. Piper KA, Boyde, Jones SJ (1995) Volumes of chick and rat osteoclasts cultured on glass. Calcified Tissue Int 56: 382–389

    CAS  Google Scholar 

  54. Piper KA, Boyde, Jones SJ (1992) The relationship between the number of nuclei of an osteoclast and its resorptive capability in vitro. Anat Embryol 186: 291–299

    Article  CAS  PubMed  Google Scholar 

  55. Sainsbury A, Schwarzer C, Couzens M, Fetissov S, Furtinger S, Jenkins A, Cox HM, Sperk G, Hokfelt T, Herzog H (2002) Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice. Proc Natl Acad Sci USA 99: 8938–8943

    Article  CAS  PubMed  Google Scholar 

  56. Baldock PA, Sainsbury A, Allison S, Lin EJ, Couzens M, Enriquez R, During M, Herzog H, Gardiner EM (2005) Hypothalamic control of bone formation: Distinct actions of leptin and Y2 receptor pathways. JBMR J0412748RZ (in press)

    Google Scholar 

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Author information

Authors and Affiliations

  1. Bone and Mineral Program, St Vincent’s Hospital, Sydney, Australia

    Susan J. Allison

  2. Neurobiology Program, Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, Australia

    Herbert Herzog

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  1. Susan J. Allison
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  2. Herbert Herzog
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Editors and Affiliations

  1. Department of Physiology and Biophysics, Georgetown University Medical Center, 3900 Reservoir Rd., NW, Washington, DC, 20057, USA

    Zofia Zukowska

  2. Wyeth Research, Building A3153, 500 Arcola Rd, Collegeville, PA, 19426, USA

    Giora Z. Feuerstein

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© 2006 Birkhäuser Verlag/Switzerland

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Allison, S.J., Herzog, H. (2006). NPY and bone. In: Zukowska, Z., Feuerstein, G.Z. (eds) NPY Family of Peptides in Neurobiology, Cardiovascular and Metabolic Disorders: from Genes to Therapeutics. Experientia Supplementum, vol 95. Birkhäuser Basel. https://doi.org/10.1007/3-7643-7417-9_13

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