PTH and PTHrP: Nonclassical Targets

  • Luisella CianferottiEmail author


Parathyroid hormone (PTH) and the polyhormone parathyroid hormone-related peptide (PTHrP) play key roles in organs not classically related to the maintenance of bone and mineral metabolism. Indeed, they exert their actions through binding the PTH/PTHrP receptor, namely, PTH1R, which is expressed in several tissues other than kidney and bone. While PTH acts as a real hormone and displays endocrine actions, PTHrP acts mainly as a paracrine/autocrine factor, regulating cell proliferation and specific functions, both in development and physiopathology. Circulating PTH has been shown to mobilize hematopoietic stem cells both in vitro and in vivo, in animals and humans, and shows promising regenerative properties in damaged tissues after ischemia/reperfusion. Specific forms of PTHrP retained within the cell play key roles in the control of cell cycle and could be addressed to control abnormal proliferation in diseases such as cancer or the initial stages of atherosclerosis. Totally unexpected properties in sustaining innate immunity have recently been demonstrated for PTH, which in concert with 1,25(OH)2 vitamin D elicit the production of antimicrobial antigens in response to pathogens in the skin barrier. Translational studies are needed in order to confirm the importance of these mechanisms in humans and to assess whether the intermittent administration of PTH could elicit specific actions in vivo.


Parathyroid hormone-related peptide Parathyroid hormone receptor Teriparatide Hematopoietic stem cells Cardiovascular PTH1R 


  1. 1.
    Bro S, Olgaard K (1997) Effect of excess PTH on nonclassical target organs. Am J Kidney Dis 30:606–620PubMedGoogle Scholar
  2. 2.
    Suva LJ, Winslow GA, Wettenhall RE et al (1987) A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 237:893–896PubMedGoogle Scholar
  3. 3.
    Asa SL, Henderson J, Goltzman D et al (1990) Parathyroid hormone-like peptide in normal and neoplastic human endocrine tissues. J Clin Endocrinol Metab 71:1112–1118PubMedGoogle Scholar
  4. 4.
    Wysolmerski JJ (2012) Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab 97:2947–2956PubMedCentralPubMedGoogle Scholar
  5. 5.
    Philbrick WM, Wysolmerski JJ, Galbraith S et al (1996) Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev 76:127–173PubMedGoogle Scholar
  6. 6.
    McCauley LK, Martin TJ (2012) Twenty-five years of PTHrP progress: from cancer hormone to multifunctional cytokine. J Bone Miner Res 27:1231–1239PubMedGoogle Scholar
  7. 7.
    El-Hashash AH, Esbrit P, Kimber SJ (2005) PTHrP promotes murine secondary trophoblast giant cell differentiation through induction of endocycle, upregulation of giant-cell-promoting transcription factors and suppression of other trophoblast cell types. Differentiation 73:154–174PubMedGoogle Scholar
  8. 8.
    Hiremath M, Wysolmerski J (2013) Parathyroid hormone-related protein specifies the mammary mesenchyme and regulates embryonic mammary development. J Mammary Gland Biol Neoplasia 18:171–177PubMedCentralPubMedGoogle Scholar
  9. 9.
    Gensure RC, Gardella TJ, Jüppner H (2005) Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem Biophys Res Commun 328:666–678PubMedGoogle Scholar
  10. 10.
    Nguyen MT, Karaplis AC (1998) The nucleus: a target site for parathyroid hormone-related peptide (PTHrP) action. J Cell Biochem 70:193–199PubMedGoogle Scholar
  11. 11.
    de Miguel F, Fiaschi-Taesch N, López-Talavera JC et al (2001) The C-terminal region of PTHrP, in addition to the nuclear localization signal, is essential for the intracrine stimulation of proliferation in vascular smooth muscle cells. Endocrinology 142:4096–4105PubMedGoogle Scholar
  12. 12.
    Stewart AF, Fiaschi-Taesch NM (2003) Minireview: parathyroid hormone-related protein as an intracrine factor—trafficking mechanisms and functional consequences. Endocrinology 144:407–411PubMedGoogle Scholar
  13. 13.
    Shen X, Qian L, Falzon M (2004) PTH-related protein enhances MCF-7 breast cancer cell adhesion, migration, and invasion via an intracrine pathway. Exp Cell Res 294:420–433PubMedGoogle Scholar
  14. 14.
    Park SI, McCauley LK (2012) Nuclear localization of parathyroid hormone-related peptide confers resistance to anoikis in prostate cancer cells. Endocr Relat Cancer 19:243–254PubMedCentralPubMedGoogle Scholar
  15. 15.
    Clemens TL, Cormier S, Eichinger A et al (2001) Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets. Br J Pharmacol 134:1113–1136PubMedCentralPubMedGoogle Scholar
  16. 16.
    Dobolyi A, Dimitrov E, Palkovits M et al (2012) The neuroendocrine functions of the parathyroid hormone 2 receptor. Front Endocrinol (Lausanne) 3:121. doi: 10.3389/fendo.2012.00121 Google Scholar
  17. 17.
    John MR, Arai M, Rubin DA et al (2002) Identification and characterization of the murine and human gene encoding the tuberoinfundibular peptide of 39 residues. Endocrinology 143:1047–1057PubMedGoogle Scholar
  18. 18.
    Mok LL, Nickols GA, Thompson JC et al (1989) Parathyroid hormone as a smooth muscle relaxant. Endocr Rev 10:420–436PubMedGoogle Scholar
  19. 19.
    Fritsch S, Lindner V, Welsch S et al (2004) Intravenous delivery of PTH/PTHrP type 1 receptor cDNA to rats decreases heart rate, blood pressure, renal tone, renin angiotensin system, and stress-induced cardiovascular responses. J Am Soc Nephrol 15:2588–2600PubMedGoogle Scholar
  20. 20.
    Noonan WT, Qian J, Stuart WD et al (2003) Altered renal hemodynamics in mice overexpressing the parathyroid hormone (PTH)/PTH-related peptide type 1 receptor in smooth muscle. Endocrinology 144:4931–4938PubMedGoogle Scholar
  21. 21.
    Jiang B, Morimoto S, Yang J et al (1998) Expression of parathyroid hormone/parathyroid hormone-related protein receptor in vascular endothelial cells. J Cardiovasc Pharmacol 31:S142–S144PubMedGoogle Scholar
  22. 22.
    Sutliff RL, Weber CS, Qian J et al (1999) Vasorelaxant properties of parathyroid hormone-related protein in the mouse: evidence for endothelium involvement independent of nitric oxide formation. Endocrinology 140:2077–2083PubMedGoogle Scholar
  23. 23.
    Kalinowski L, Dobrucki LW, Malinski T (2001) Nitric oxide as a second messenger in parathyroid hormone-related protein signaling. J Endocrinol 170:433–440PubMedGoogle Scholar
  24. 24.
    Wolzt M, Schmetterer L, Dorner G et al (1997) Hemodynamic effects of parathyroid hormone-related peptide-(1–34) in humans. J Clin Endocrinol Metab 82:2548–2551PubMedGoogle Scholar
  25. 25.
    Raison D, Coquard C, Hochane M et al (2013) Knockdown of parathyroid hormone related protein in smooth muscle cells alters renal hemodynamics but not blood pressure. Am J Physiol Renal Physiol 305:F333–F342PubMedGoogle Scholar
  26. 26.
    Gray C, Bratt D, Lees J et al (2013) Loss of function of parathyroid hormone receptor 1 induces Notch-dependent aortic defects during zebrafish vascular development. Arterioscler Thromb Vasc Biol 33:1257–1263PubMedGoogle Scholar
  27. 27.
    Schordan E, Welsch S, Rothhut S et al (2004) Role of parathyroid hormone-related protein in the regulation of stretch-induced renal vascular smooth muscle cell proliferation. J Am Soc Nephrol 15:3016–3025PubMedGoogle Scholar
  28. 28.
    Massfelder T, Dann P, Wu TL et al (1997) Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: a critical role for nuclear targeting. Proc Natl Acad Sci U S A 94:13630–13635PubMedCentralPubMedGoogle Scholar
  29. 29.
    Ishikawa M, Akishita M, Kozaki K et al (2000) Expression of parathyroid hormone-related protein in human and experimental atherosclerotic lesions: functional role in arterial intimal thickening. Atherosclerosis 152:97–105PubMedGoogle Scholar
  30. 30.
    Fiaschi-Taesch N, Takane KK, Masters S et al (2004) Parathyroid-hormone-related protein as a regulator of pRb and the cell cycle in arterial smooth muscle. Circulation 110:177–185PubMedGoogle Scholar
  31. 31.
    Fiaschi-Taesch N, Sicari BM, Ubriani K et al (2006) Cellular mechanism through which parathyroid hormone-related protein induces proliferation in arterial smooth muscle cells: definition of an arterial smooth muscle PTHrP/p27kip1 pathway. Circ Res 99:933–942PubMedGoogle Scholar
  32. 32.
    Sicari BM, Troxell R, Salim F et al (2012) c-myc and skp2 coordinate p27 degradation, vascular smooth muscle proliferation, and neointima formation induced by the parathyroid hormone-related protein. Endocrinology 153:861–872PubMedGoogle Scholar
  33. 33.
    Stuart WD, Maeda S, Khera P et al (2000) Parathyroid hormone-related protein induces G1 phase growth arrest of vascular smooth muscle cells. Am J Physiol Endocrinol Metab 279:E60–E67PubMedGoogle Scholar
  34. 34.
    Bakre MM, Zhu Y, Yin H, Burton DW et al (2002) Parathyroid hormone-related peptide is a naturally occurring, protein kinase A-dependent angiogenesis inhibitor. Nat Med 8:995–1003PubMedGoogle Scholar
  35. 35.
    Fiaschi-Taesch N, Sicari B, Ubriani K et al (2009) Mutant parathyroid hormone-related protein, devoid of the nuclear localization signal, markedly inhibits arterial smooth muscle cell cycle and neointima formation by coordinate up-regulation of p15Ink4b and p27kip1. Endocrinology 150:1429–1439PubMedGoogle Scholar
  36. 36.
    Song GJ, Fiaschi-Taesch N, Bisello A (2009) Endogenous parathyroid hormone-related protein regulates the expression of PTH type 1 receptor and proliferation of vascular smooth muscle cells. Mol Endocrinol 23:1681–1690PubMedCentralPubMedGoogle Scholar
  37. 37.
    Song GJ, Barrick S, Leslie KL et al (2010) EBP50 inhibits the anti-mitogenic action of the parathyroid hormone type 1 receptor in vascular smooth muscle cells. J Mol Cell Cardiol 49:1012–1021PubMedCentralPubMedGoogle Scholar
  38. 38.
    Martín-Ventura JL, Ortego M, Esbrit P et al (2003) Possible role of parathyroid hormone-related protein as a proinflammatory cytokine in atherosclerosis. Stroke 34:1783–1789PubMedGoogle Scholar
  39. 39.
    Martin-Ventura JL, Blanco-Colio LM, Aparicio C et al (2008) LDL induces parathyroid hormone-related protein expression in vascular smooth muscle cells: modulation by simvastatin. Atherosclerosis 198:264–271PubMedGoogle Scholar
  40. 40.
    Conzelmann C, Krasteva G, Weber K et al (2009) Parathyroid hormone-related protein (PTHrP)-dependent regulation of bcl-2 and tissue inhibitor of metalloproteinase (TIMP)-1 in coronary endothelial cells. Cell Physiol Biochem 24:493–502PubMedGoogle Scholar
  41. 41.
    Liu F, Fu P, Fan W et al (2012) Involvement of parathyroid hormone-related protein in vascular calcification of chronic haemodialysis patients. Nephrology (Carlton) 17:552–560Google Scholar
  42. 42.
    Jono S, Nishizawa Y, Shioi A et al (1997) Parathyroid hormone-related peptide as a local regulator of vascular calcification. Its inhibitory action on in vitro calcification by bovine vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 17:1135–1142PubMedGoogle Scholar
  43. 43.
    Rashid G, Bernheim J, Green J et al (2007) Parathyroid hormone stimulates the endothelial nitric oxide synthase through protein kinase A and C pathways. Nephrol Dial Transplant 22:2831–2837PubMedGoogle Scholar
  44. 44.
    Prisby R, Menezes T, Campbell J (2013) Vasodilation to PTH (1–84) in bone arteries is dependent upon the vascular endothelium and is mediated partially via VEGF signaling. Bone 54:68–75PubMedGoogle Scholar
  45. 45.
    Roche B, Vanden-Bossche A, Malaval L et al (2014) Parathyroid hormone 1–84 targets bone vascular structure and perfusion in mice: impacts of its administration regimen and of ovariectomy. J Bone Miner Res. doi: 10.1002/jbmr.2191 PubMedGoogle Scholar
  46. 46.
    Tomaschitz A, Ritz E, Pieske B et al (2014) Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease. Metabolism 63:20–31PubMedGoogle Scholar
  47. 47.
    Rashid G, Bernheim J, Green J et al (2007) Parathyroid hormone stimulates endothelial expression of atherosclerotic parameters through protein kinase pathways. Am J Physiol Renal Physiol 292:F1215–F1218PubMedGoogle Scholar
  48. 48.
    Rashid G, Bernheim J, Green J et al (2008) Parathyroid hormone stimulates the endothelial expression of vascular endothelial growth factor. Eur J Clin Invest 38:798–803PubMedGoogle Scholar
  49. 49.
    Jean G, Bresson E, Lorriaux C et al (2012) Increased levels of serum parathyroid hormone and fibroblast growth factor-23 are the main factors associated with the progression of vascular calcification in long-hour hemodialysis patients. Nephron Clin Pract 120:c132–c138PubMedGoogle Scholar
  50. 50.
    Bui TD, Shallal A, Malik AN et al (1993) Parathyroid hormone-related peptide gene expression in human fetal and adult heart. Cardiovasc Res 127:1204–1208Google Scholar
  51. 51.
    Schlüter KD, Wingender E, Tegge W et al (1996) Parathyroid hormone-related protein antagonizes the action of parathyroid hormone on adult cardiomyocytes. J Biol Chem 271:3074–3078PubMedGoogle Scholar
  52. 52.
    Crass MF III, Pang PKT (1980) Parathyroid hormone: a coronary artery vasodilator. Science 207:1087–1089PubMedGoogle Scholar
  53. 53.
    Deftos LJ, Burton DW, Brandt DW (1993) Parathyroid hormone-like protein (PLP) is a secretory product of atrial myocytes. J Clin Invest 92:727–735PubMedCentralPubMedGoogle Scholar
  54. 54.
    Schlüter K, Katzer C, Frischkopf K et al (2000) Expression, release, and biological activity of parathyroid hormone-related peptide from coronary endothelial cells. Circ Res 86:946–951PubMedGoogle Scholar
  55. 55.
    Jansen J, Gres P, Umschlag C et al (2003) Parathyroid hormone-related peptide improves contractile function of stunned myocardium in rats and pigs. Am J Physiol Heart Circ Physiol 284:H49–H55PubMedGoogle Scholar
  56. 56.
    Monego G, Arena V, Pasquini S et al (2009) Ischemic injury activates PTHrP and PTH1R expression in human ventricular cardiomyocytes. Basic Res Cardiol 104:427–434PubMedGoogle Scholar
  57. 57.
    Degenhardt H, Jansen J, Schulz R et al (2002) Mechanosensitive release of parathyroid hormone-related peptide from coronary endothelial cells. Am J Physiol Heart Circ Physiol 283:H1489–H1496PubMedGoogle Scholar
  58. 58.
    Abdallah Y, Ross G, Dolf A et al (2006) N-terminal parathyroid hormone-related peptide hyperpolarizes endothelial cells and causes a reduction of the coronary resistance of the rat heart via endothelial hyperpolarization. Peptides 27:2927–2934PubMedGoogle Scholar
  59. 59.
    Ogino K, Ogura K, Kinugasa Y et al (2002) Parathyroid hormone-related protein is produced in the myocardium and increased in patients with congestive heart failure. J Clin Endocrinol Metab 87:4722–4727PubMedGoogle Scholar
  60. 60.
    Grohe C, van Eickels M, Wenzel S et al (2004) Sex-specific differences in ventricular expression and function of parathyroid hormone-related peptide. Cardiovasc Res 61:307–316PubMedGoogle Scholar
  61. 61.
    Schreckenberg R, Wenzel S, da Costa Rebelo RM et al (2009) Cell-specific effects of nitric oxide deficiency on parathyroid hormone-related peptide (PTHrP) responsiveness and PTH1 receptor expression in cardiovascular cells. Endocrinology 150:3735–3741PubMedGoogle Scholar
  62. 62.
    Röthig A, Schreckenberg R, Weber K et al (2012) Effects of nicotine on PTHrP and PTHrP receptor expression in rat coronary endothelial cells. Cell Physiol Biochem 29:485–492PubMedGoogle Scholar
  63. 63.
    Ross G, Schlüter KD (2005) Cardiac-specific effects of parathyroid hormone-related peptide: modification by aging and hypertension. Cardiovasc Res 66:334–344PubMedGoogle Scholar
  64. 64.
    Grandi NC, Breitling LP, Hahmann H et al (2011) Serum parathyroid hormone and risk of adverse outcomes in patients with stable coronary heart disease. Heart 97:1215–1221PubMedGoogle Scholar
  65. 65.
    Tastan I, Schreckenberg R, Mufti S et al (2009) Parathyroid hormone improves contractile performance of adult rat ventricular cardiomyocytes at low concentrations in a non-acute way. Cardiovasc Res 82:77–83PubMedGoogle Scholar
  66. 66.
    Akino K, Ohtsuru A, Kanda K et al (2000) Parathyroid hormone-related peptide is a potent tumor angiogenic factor. Endocrinology 141:4313–4316PubMedGoogle Scholar
  67. 67.
    Kremer R, Li J, Camirand A, Karaplis AC (2011) Parathyroid hormone related protein (PTHrP) in tumor progression. Adv Exp Med Biol 720:145–160PubMedGoogle Scholar
  68. 68.
    Park SI, Lee C, Sadler WD et al (2013) Parathyroid hormone-related protein drives a CD11b + Gr1+ cell-mediated positive feedback loop to support prostate cancer growth. Cancer Res 73:6574–6583PubMedGoogle Scholar
  69. 69.
    Ongkeko WM, Burton D, Kiang A et al (2014) Parathyroid hormone related-protein promotes epithelial-to-mesenchymal transition in prostate cancer. PLoS One 9(1):e85803PubMedCentralPubMedGoogle Scholar
  70. 70.
    Downs TM, Burton DW, Araiza FL et al (2011) PTHrP stimulates prostate cancer cell growth and upregulates aldo-keto reductase 1C3. Cancer Lett 306:52–59PubMedGoogle Scholar
  71. 71.
    Danilin S, Sourbier C, Thomas L et al (2009) von Hippel-Lindau tumor suppressor gene-dependent mRNA stabilization of the survival factor parathyroid hormone-related protein in human renal cell carcinoma by the RNA-binding protein HuR. Carcinogenesis 30:387–396PubMedGoogle Scholar
  72. 72.
    Mula RV, Bhatia V, Falzon M (2010) PTHrP promotes colon cancer cell migration and invasion in an integrin α6β4-dependent manner through activation of Rac1. Cancer Lett 298:119–127PubMedCentralPubMedGoogle Scholar
  73. 73.
    Zhang H, Yu C, Dai J et al (2013) Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of β-catenin activation of the DKK1 promoter in prostate cancer. Oncogene. doi: 10.1038/onc.2013.203 Google Scholar
  74. 74.
    Bhatia V, Mula RV, Falzon M (2013) Parathyroid hormone-related protein regulates integrin α6 and β4 levels via transcriptional and post-translational pathways. Exp Cell Res 319:1419–1430PubMedCentralPubMedGoogle Scholar
  75. 75.
    Bhatia V, Mula RV, Falzon M (2011) 1,25-Dihydroxyvitamin D(3) regulates PTHrP expression via transcriptional, post-transcriptional and post-translational pathways. Mol Cell Endocrinol 342:32–40PubMedCentralPubMedGoogle Scholar
  76. 76.
    Kuo PL, Liao SH, Hung JY et al (2013) MicroRNA-33a functions as a bone metastasis suppressor in lung cancer by targeting parathyroid hormone related protein. Biochim Biophys Acta 1830:3756–3766PubMedGoogle Scholar
  77. 77.
    Li J, Karaplis AC, Huang DC et al (2011) PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target. J Clin Invest 121:4655–4669PubMedCentralPubMedGoogle Scholar
  78. 78.
    Takagaki K, Takashima T, Onoda N et al (2012) Parathyroid hormone-related protein expression, in combination with nodal status, predicts bone metastasis and prognosis of breast cancer patients. Exp Ther Med 3:963–968PubMedCentralPubMedGoogle Scholar
  79. 79.
    Mak IW, Cowan RW, Turcotte RE et al (2011) PTHrP induces autocrine/paracrine proliferation of bone tumor cells through inhibition of apoptosis. PLoS One 6:e19975. doi: 10.1371/journal.pone.0019975 PubMedCentralPubMedGoogle Scholar
  80. 80.
    Mak IW, Turcotte RE, Ghert M (2012) Transcriptomic and proteomic analyses in bone tumor cells: deciphering parathyroid hormone-related protein regulation of the cell cycle and apoptosis. J Bone Miner Res 27:1976–1991PubMedGoogle Scholar
  81. 81.
    Mak IW, Turcotte RE, Ghert M (2013) Parathyroid hormone-related protein (PTHrP) modulates adhesion, migration and invasion in bone tumor cells. Bone 55:198–207PubMedGoogle Scholar
  82. 82.
    Jolette J, Wilker CE, Smith SY et al (2006) Defining a noncarcinogenic dose of recombinant human parathyroid hormone 1–84 in a 2-year study in Fischer 344 rats. Toxicol Pathol 34:929–940PubMedGoogle Scholar
  83. 83.
    Watanabe A, Yoneyama S, Nakajima M et al (2012) Osteosarcoma in Sprague–Dawley rats after long-term treatment with teriparatide (human parathyroid hormone (1–34)). J Toxicol Sci 37:617–629PubMedGoogle Scholar
  84. 84.
    Andrews EB, Gilsenan AW, Midkiff K et al (2012) The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and findings from the first 7 years. J Bone Miner Res 27:2429–2437PubMedCentralPubMedGoogle Scholar
  85. 85.
    Calvi LM, Adams GB, Weibrecht KW et al (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425:841–846PubMedGoogle Scholar
  86. 86.
    Adams GB, Martin RP, Alley IR et al (2007) Therapeutic targeting of a stem cell niche. Nat Biotechnol 25:238–243PubMedGoogle Scholar
  87. 87.
    Brunner S, Zaruba MM, Huber B et al (2008) Parathyroid hormone effectively induces mobilization of progenitor cells without depletion of bone marrow. Exp Hematol 36:1157–1166PubMedGoogle Scholar
  88. 88.
    Li JY, Adams J, Calvi LM et al (2012) PTH expands short-term murine hemopoietic stem cells through T cells. Blood 120:4352–4362PubMedCentralPubMedGoogle Scholar
  89. 89.
    Yu EW, Kumbhani R, Siwila-Sackman E et al (2014) Teriparatide (PTH 1–34) treatment increases peripheral hematopoietic stem cells in postmenopausal women. J Bone Miner Res. doi: 10.1002/jbmr.2171 PubMedCentralGoogle Scholar
  90. 90.
    Feola M, Crass MF 3rd (1986) Parathyroid hormone reduces acute ischemic injury of the myocardium. Surg Gynecol Obstet 163:523–530PubMedGoogle Scholar
  91. 91.
    Zaruba MM, Huber BC, Brunner S et al (2008) Parathyroid hormone treatment after myocardial infarction promotes cardiac repair by enhanced neovascularization and cell survival. Cardiovasc Res 77:722–731PubMedGoogle Scholar
  92. 92.
    Brunner S, Weinberger T, Huber BC et al (2012) The cardioprotective effects of parathyroid hormone are independent of endogenous granulocyte-colony stimulating factor release. Cardiovasc Res 93:330–339PubMedGoogle Scholar
  93. 93.
    Weir EC, Brines ML, Ikeda K et al (1990) Parathyroid hormone-related peptide gene is expressed in the mammalian central nervous system. Proc Natl Acad Sci U S A 87:108–112PubMedCentralPubMedGoogle Scholar
  94. 94.
    Chatterjee O, Nakchbandi IA, Philbrick WM et al (2002) Endogenous parathyroid hormone-related protein functions as a neuroprotective agent. Brain Res 930:58–66PubMedGoogle Scholar
  95. 95.
    Funk JL, Trout CR, Wei H et al (2001) Parathyroid hormone-related protein (PTHrP) induction in reactive astrocytes following brain injury: a possible mediator of CNS inflammation. Brain Res 915:195–209PubMedGoogle Scholar
  96. 96.
    Macica CM, Liang G, Lankford KL et al (2006) Induction of parathyroid hormone-related peptide following peripheral nerve injury: role as a modulator of Schwann cell phenotype. Glia 53:637–648PubMedGoogle Scholar
  97. 97.
    Wang LL, Chen D, Lee J et al (2014) Mobilization of endogenous bone marrow derived endothelial progenitor cells and therapeutic potential of parathyroid hormone after ischemic stroke in mice. PLoS One 9(2):e87284. doi: 10.1371/journal.pone.0087284 PubMedCentralPubMedGoogle Scholar
  98. 98.
    Esbrit P, Santos S, Ortega A et al (2001) Parathyroid hormone-related protein as a renal regulating factor. From vessels to glomeruli and tubular epithelium. Am J Nephrol 21:179–184PubMedGoogle Scholar
  99. 99.
    Soifer NE, Van Why SK, Ganz MB et al (1993) Expression of parathyroid hormone-related protein in the rat glomerulus and tubule during recovery from renal ischemia. J Clin Invest 92:2850–2857PubMedCentralPubMedGoogle Scholar
  100. 100.
    Largo R, Gómez-Garre D, Santos S et al (1999) Renal expression of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor in a rat model of tubulointerstitial damage. Kidney Int 55:82–90PubMedGoogle Scholar
  101. 101.
    Santos S, Bosch RJ, Ortega A et al (2001) Up-regulation of parathyroid hormone-related protein in folic acid-induced acute renal failure. Kidney Int 60:982–995PubMedGoogle Scholar
  102. 102.
    Lorenzo O, Ruiz-Ortega M, Esbrit P et al (2002) Angiotensin II increases parathyroid hormone-related protein (PTHrP) and the type 1 PTH/PTHrP receptor in the kidney. J Am Soc Nephrol 13:1595–1607PubMedGoogle Scholar
  103. 103.
    Izquierdo A, López-Luna P, Ortega A et al (2006) The parathyroid hormone-related protein system and diabetic nephropathy outcome in streptozotocin-induced diabetes. Kidney Int 69:2171–2177PubMedGoogle Scholar
  104. 104.
    Rámila D, Ardura JA, Esteban V et al (2008) Parathyroid hormone-related protein promotes inflammation in the kidney with an obstructed ureter. Kidney Int 73:835–847PubMedGoogle Scholar
  105. 105.
    Ortega A, Rámila D, Izquierdo A et al (2005) Role of the renin-angiotensin system on the parathyroid hormone-related protein overexpression induced by nephrotoxic acute renal failure in the rat. J Am Soc Nephrol 16:939–949PubMedGoogle Scholar
  106. 106.
    Bosch RJ, Ortega A, Izquierdo A et al (2011) A transgenic mouse model for studying the role of the parathyroid hormone-related protein system in renal injury. J Biomed Biotechnol 2011:290874. doi: 10.1155/2011/290874 PubMedCentralPubMedGoogle Scholar
  107. 107.
    Fiaschi-Taesch NM, Santos S, Reddy V et al (2004) Prevention of acute ischemic renal failure by targeted delivery of growth factors to the proximal tubule in transgenic mice: the efficacy of parathyroid hormone-related protein and hepatocyte growth factor. J Am Soc Nephrol 15:112–125PubMedGoogle Scholar
  108. 108.
    Ortega A, Rámila D, Ardura JA et al (2006) Role of parathyroid hormone-related protein in tubulointerstitial apoptosis and fibrosis after folic acid-induced nephrotoxicity. J Am Soc Nephrol 17:1594–1603PubMedGoogle Scholar
  109. 109.
    Ardura JA, Berruguete R, Rámila D et al (2008) Parathyroid hormone-related protein interacts with vascular endothelial growth factor to promote fibrogenesis in the obstructed mouse kidney. Am J Physiol Renal Physiol 295:F415–F425PubMedGoogle Scholar
  110. 110.
    Ardura JA, Rayego-Mateos S, Rámila D et al (2010) Parathyroid hormone-related protein promotes epithelial-mesenchymal transition. J Am Soc Nephrol 21:237–248PubMedCentralPubMedGoogle Scholar
  111. 111.
    Ortega A, Romero M, Izquierdo A et al (2012) Parathyroid hormone-related protein is a hypertrophy factor for human mesangial cells: implications for diabetic nephropathy. J Cell Physiol 227:1980–1987PubMedGoogle Scholar
  112. 112.
    Romero M, Ortega A, Olea N et al (2013) Novel role of parathyroid hormone-related protein in the pathophysiology of the diabetic kidney: evidence from experimental and human diabetic nephropathy. J Diabetes Res 2013:162846. doi: 10.1155/2013/162846 PubMedCentralPubMedGoogle Scholar
  113. 113.
    Hochane M, Raison D, Coquard C et al (2013) Parathyroid hormone-related protein is a mitogenic and a survival factor of mesangial cells from male mice: role of intracrine and paracrine pathways. Endocrinology 154:853–864PubMedGoogle Scholar
  114. 114.
    Ardura JA, Sanz AB, Ortiz A et al (2013) Parathyroid hormone-related protein protects renal tubuloepithelial cells from apoptosis by activating transcription factor Runx2. Kidney Int 83:825–834PubMedGoogle Scholar
  115. 115.
    Fujinaka Y, Sipula D, Garcia-Ocaña A et al (2004) Characterization of mice doubly transgenic for parathyroid hormone-related protein and murine placental lactogen: a novel role for placental lactogen in pancreatic beta-cell survival. Diabetes 53:3120–3130PubMedGoogle Scholar
  116. 116.
    Drucker DJ, Asa SL, Henderson J et al (1989) The parathyroid hormone-like peptide gene is expressed in the normal and neoplastic human endocrine pancreas. Mol Endocrinol 3:1589–1595PubMedGoogle Scholar
  117. 117.
    Villanueva-Peñacarrillo ML, Cancelas J, de Miguel F et al (1999) Parathyroid hormone-related peptide stimulates DNA synthesis and insulin secretion in pancreatic islets. J Endocrinol 163:403–408PubMedGoogle Scholar
  118. 118.
    Vasavada RC, Cavaliere C, D’Ercole AJ et al (1996) Overexpression of parathyroid hormone-related protein in the pancreatic islets of transgenic mice causes islet hyperplasia, hyperinsulinemia, and hypoglycemia. J Biol Chem 271:1200–1208PubMedGoogle Scholar
  119. 119.
    Porter SE, Sorenson RL, Dann P et al (1998) Progressive pancreatic islet hyperplasia in the islet-targeted, parathyroid hormone-related protein-overexpressing mouse. Endocrinology 139:3743–3751PubMedGoogle Scholar
  120. 120.
    Cebrian A, García-Ocaña A, Takane KK et al (2002) Overexpression of parathyroid hormone-related protein inhibits pancreatic beta-cell death in vivo and in vitro. Diabetes 51:3003–3013PubMedGoogle Scholar
  121. 121.
    Sawada Y, Zhang B, Okajima F et al (2001) PTHrP increases pancreatic beta-cell-specific functions in well-differentiated cells. Mol Cell Endocrinol 182:265–275PubMedGoogle Scholar
  122. 122.
    Zhang B, Hosaka M, Sawada Y et al (2003) Parathyroid hormone-related protein induces insulin expression through activation of MAP kinase-specific phosphatase-1 that dephosphorylates c-Jun NH2-terminal kinase in pancreatic beta-cells. Diabetes 52:2720–2730PubMedGoogle Scholar
  123. 123.
    Guthalu Kondegowda N, Joshi-Gokhale S, Harb G et al (2010) Parathyroid hormone-related protein enhances human ß-cell proliferation and function with associated induction of cyclin-dependent kinase 2 and cyclin E expression. Diabetes 59:3131–3138PubMedCentralPubMedGoogle Scholar
  124. 124.
    Williams K, Abanquah D, Joshi-Gokhale S et al (2011) Systemic and acute administration of parathyroid hormone-related peptide(1–36) stimulates endogenous beta cell proliferation while preserving function in adult mice. Diabetologia 54:2867–2877PubMedGoogle Scholar
  125. 125.
    Shor R, Halabe A, Aberbuh E et al (2006) PTHrP and insulin levels following oral glucose and calcium administration. Eur J Intern Med 17:408–411PubMedGoogle Scholar
  126. 126.
    Rosenberg J, Pines M, Hurwitz S (1987) Response of adrenal cells to parathyroid hormone stimulation. J Endocrinol 112:431–437PubMedGoogle Scholar
  127. 127.
    Isales CM, Barrett PQ, Brines M et al (1991) Parathyroid hormone modulates angiotensin II induced aldosterone secretion from the adrenal glomerulosa cell. Endocrinology 129:489–495PubMedGoogle Scholar
  128. 128.
    Olgaard K, Lewin E, Bro S et al (1994) Enhancement of the stimulatory effect of calcium on aldosterone secretion by parathyroid hormone. Miner Electrolyte Metab 20:309–314PubMedGoogle Scholar
  129. 129.
    Mazzocchi G, Aragona F, Malendowicz LK et al (2001) PTH and PTH-related peptide enhance steroid secretion from human adrenocortical cells. Am J Physiol Endocrinol Metab 280:E209–E213PubMedGoogle Scholar
  130. 130.
    Rizk-Rabin M, Assie G, Rene-Corail F et al (2008) Differential expression of parathyroid hormone-related protein in adrenocortical tumors: autocrine/paracrine effects on the growth and signaling pathways in H295R cells. Cancer Epidemiol Biomarkers Prev 17:2275–2285PubMedGoogle Scholar
  131. 131.
    Gennari C, Nami R, Gonnelli S (1995) Hypertension and primary hyperparathyroidism: the role of adrenergic and renin–angiotensin–aldosterone systems. Miner Electrolyte Metab 21:77–81PubMedGoogle Scholar
  132. 132.
    Kovacs L, Goth MI, Szabolcs I et al (1998) The effect of surgical treatment on secondary hyperaldosteronism and relative hyperinsulinemia in primary hyperparathyroidism. Eur J Endocrinol 138:543–547PubMedGoogle Scholar
  133. 133.
    Muehleisen B, Bikle DD, Aguilera C et al (2012) PTH/PTHrP and vitamin D control antimicrobial peptide expression and susceptibility to bacterial skin infection. Sci Transl Med 4:135ra66. doi: 10.1126/scitranslmed.3003759 PubMedCentralPubMedGoogle Scholar
  134. 134.
    Liu PT, Stenger S, Li H et al (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311:1770–1773PubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2015

Authors and Affiliations

  1. 1.Unit of Bone and Mineral Metabolism, Department of Surgery and Translational MedicineUniversity of FlorenceFlorenceItaly

Personalised recommendations