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The Parathyroid Hormone Family of Ligands and Receptors

School of Medical Sciences, Rmit University, Bundoora West, Victoria 3083 Australia

Special Issues: Developmental and Physiological roles of PTH ligands and receptors: New Insights

The PTH family of ligands and receptors have a wide range of vital functions from calcium homeostasis to tissue and bone development from the embryo to adult. This family has undergone whole genome duplication events predating vertebrate evolution, indicating more primitive and ancient functions other than skeletal development. The N-terminal region of the ligands, have been widely studied by biophysical and functional analysis, resulting in the discovery of key characteristics essential for ligand-receptor activation being elucidated. Multi-substituted amino acid analogs with differential binding affinities and either antagonistic or agonistic signalling potencies have been created based on these findings allowing for improvement on potential therapies affected by the PTH system in skeletal and embryonic development. The PTH family has diversely evolved to cover a wide range of pivotal pathways crucial to growth and development throughout all animal life.
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Keywords Parathyroid hormone (PTH); parathyroid hormone related protein (PTHrP); tuberoinfundibular peptide 39 (TIP39); parathyroid hormone like peptide (PTH-L); G-protein coupled receptors (GPCRs); parathyroid hormone receptors (PTHR1, PTHR2, PTHR3); epithelial-to-mesenchymal transition (EMT); zebrafish, xenopus; elephant shark

Citation: Damian G. DSouza. The Parathyroid Hormone Family of Ligands and Receptors. AIMS Medical Science, 2015, 2(3): 118-130. doi: 10.3934/medsci.2015.3.118


  • 1. Gardella TJ, Juppner H (2001) Molecular properties of the PTH/PTHrP receptor. Trends Endocrinol Metab 12(5): p. 210-217.
  • 2. Gensure RC, Gardella TJ, Juppner H (2005) Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem Biophys Res Commun 328(3): p. 666-678.
  • 3. Guerreiro PM, Renfro JL, DM Power, et al. (2007) The parathyroid hormone family of peptides: structure, tissue distribution, regulation, and potential functional roles in calcium and phosphate balance in fish. Am J Physiol Regul Integr Comp Physiol 292(2): p. R679-696.
  • 4. Jerome CP, DB Burr, Bibber TV, et al. (2001) Treatment with human parathyroid hormone (1-34) for 18 months increases cancellous bone volume and improves trabecular architecture in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone 28(2): p. 150-159.
  • 5. Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423(6937): p. 332-336.
  • 6. Philbrick WM, Wysolmerski J J, Galbraith S, et al. (1996) Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev 76(1): p. 127-173.
  • 7. On JS, Chow BK, Lee LT (2015) Evolution of parathyroid hormone receptor family and their ligands in vertebrate. Front Endocrinol (Lausanne) 6: p. 28.
  • 8. 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. Endocrin 143(3): p. 1047-1057.
  • 9. Papasani MR, Robert CG, John HB, et al. (2004) Identification and characterization of the zebrafish and fugu genes encoding tuberoinfundibular peptide 39. Endocrin 145(11): p. 5294-5304.
  • 10. Gensure RC, Cooper WC, Nickols GA, et al. (2004) Identification and characterization of two parathyroid hormone-like molecules in zebrafish. Endocrin 145(4): p. 1634-9.
  • 11. Shoemaker JM, Riley LG, Hirano T, et al. (2005) Differential expression of tuberoinfundibular peptide 38 and glucose-6-phosphatase in tilapia. Gen Comp Endocrinol 146(2): p. 186-94.
  • 12. Bhattacharya P, Yan Y-L, David AR, et al. (2001) Evolution of the vertebrate pth2 (tip39) gene family and the regulation of PTH type 2 receptor (pth2r) and its endogenous ligand pth2 by hedgehog signaling in zebrafish development. J Endocrinol 211(2): p. 187-200.
  • 13. Brommage R, Lees CG, Hotchkiss CE, et al. (1999) Daily treatment with human recombinant parathyroid hormone-(1-34), LY333334, for 1 year increases bone mass in ovariectomized monkeys. J Clin Endocrinol Metab 84(10): p. 3757-3763.
  • 14. Brown EM (1999) Physiology and pathophysiology of the extracellular calcium-sensing receptor. Am J Med 106(2): p. 238-253.
  • 15. Gunther T, Chen ZF, Kim G, et al. (2000) Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 406(6792): p. 199-203.
  • 16. Tucci J, Russell A, Senior SV, et al. (1996) The expression of parathyroid hormone and parathyroid hormone-related protein in developing rat parathyroid glands. J Mol Endocrinol 17(2): p. 149-157.
  • 17. Harvey S, Hayer S, Sloley BD (1993) Dopaminergic actions of parathyroid hormone in the rat medial basal hypothalamus in vitro. Regul Pept 43(1-2): p. 49-56.
  • 18. Henriksen K, Neutzsky-Wulff AV, Bonewald LF, et al. (2009) Local communication on and within bone controls bone remodeling. Bone 44(6): p. 1026-1033.
  • 19. Hayden RS, Fortin JP, Harwood B, et al. (2014) Cell-tethered ligands modulate bone remodeling by osteoblasts and osteoclasts. Adv Funct Mater 24(4): p. 472-479.
  • 20. Sims NA, Vrahnas C (2014) Regulation of cortical and trabecular bone mass by communication between osteoblasts, osteocytes and osteoclasts. Arch Biochem Biophys 561: p. 22-28.
  • 21. Chen H, Senda T, Kubo KY (2015) The osteocyte plays multiple roles in bone remodeling and mineral homeostasis. Med Mol Morphol 48(2): p. 61-68.
  • 22. Danks JA, Damian GD, Gunn HJ, et al. (2011) Evolution of the parathyroid hormone family and skeletal formation pathways. Gen Comp Endocrinol 170(1): p. 79-91.
  • 23. Han SW, Kim SJ, Lee DJ, et al. (2014) The Relationship between Serum 25-Hydroxyvitamin D, Parathyroid Hormone and the Glomerular Filtration Rate in Korean Adults: The Korea National Health and Nutrition Examination Survey between 2009 and 2011. Korean J Fam Med 35(2): p. 98-106.
  • 24. Steingrimsdottir L, Gunnarsson O, Indridason OS, et al. (2005) Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. Jama 294(18): p. 2336-2341.
  • 25. Stewart AF, Horst R, Deftos LJ, et al. (1980) Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups. N Engl J Med 303(24): p. 1377-1383.
  • 26. de la Mata J, Mundy GR, Guise TA, et al. (1995) Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo. J Clin Invest 95(6): p. 2846-2852.
  • 27. Schipani E, Provot S (2003) PTHrP, PTH, and the PTH/PTHrP receptor in endochondral bone development. Birth Defects Res C Embryo Today 69(4): p. 352-362.
  • 28. Lanske B, Pajevic PD, Kovacs CS, et al. (1998) The parathyroid hormone (PTH)/PTH-related peptide receptor mediates actions of both ligands in murine bone. Endocrin 139(12): p. 5194-5204.
  • 29. Karaplis AC, Kronenberg HM, Mulligan RC, et al. (1994) Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 8(3): p. 277-289.
  • 30. 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): p. e85803.
  • 31. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6): p. 442-454.
  • 32. Yilmaz M, Christofori G (2009) EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28(1-2): p. 15-33.
  • 33. McCauley LK, Martin TJ (2012) Twenty-five years of PTHrP progress: from cancer hormone to multifunctional cytokine. J Bone Miner Res 27(6): p. 1231-1239.
  • 34. Agouni A, Sourbier C, Danilin S, et al. (2007) Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K Akt pathway: evidence for a critical role for integrin-linked kinase and nuclear factor kappa B. Carcinogenesis 28(9): p. 1893-1901.
  • 35. 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(6): p. 1113-1136.
  • 36. Goomer RS, Shen X, Falzon M, et al. (2000) The tetrabasic KKKK(147-150) motif determines intracrine regulatory effects of PthrP 1-173 on chondrocyte PPi metabolism and matrix synthesis. Endocrin 141(12): p. 4613-4622.
  • 37. Watson PH, Hodsman AB, Fraher LJ, et al. (2000) Nuclear localization of the type 1 PTH/PTHrP receptor in rat tissues. J Bone Miner Res 15(6): p. 1033-1044.
  • 38. Juppner H, Kronenberg HM, Segre GV, et al. (1991) A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254(5034): p. 1024-1026.
  • 39. Pilz P, Meyer-Marcotty P, Eigenthaler M, et al. (2014) Differential diagnosis of primary failure of eruption (PFE) with and without evidence of pathogenic mutations in the PTHR1 gene. J Orofac Orthop 75(3): p. 226-239.
  • 40. Piserchio A, Usdin T, Mierke DF (2000) Structure of tuberoinfundibular peptide of 39 residues. J Biol Chem 275(35): p. 27284-27290.
  • 41. Jonsson KB, John MR, Gensure R, et al. (2001) Tuberoinfundibular peptide 39 binds to the parathyroid hormone (PTH)/PTH-related peptide receptor, but functions as an antagonist. Endocrin 142(2): p. 704-709.
  • 42. Gardella TJ, et al. (1996) Converting parathyroid hormone-related peptide (PTHrP) into a potent PTH-2 receptor agonist. J Biol Chem 271(33): p. 19888-93.
  • 43. Tenne M, McGuigan F, Jansson L, et al. (2008) Genetic variation in the PTH pathway and bone phenotypes in elderly women: evaluation of PTH, PTHLH, PTHR1 and PTHR2 genes. Bone 42(4): p. 719-727.
  • 44. Usdin TB, Gruber C, Bonner TI (1995) Identification and functional expression of a receptor selectively recognizing parathyroid hormone, the PTH2 receptor. J Biol Chem 270(26): p. 15455-15458.
  • 45. Usdin TB, Hoare SR, Wang T, et al. (1999) TIP39: a new neuropeptide and PTH2-receptor agonist from hypothalamus. Nat Neurosci 2(11): p. 941-943.
  • 46. Usdin TB (1997) Evidence for a parathyroid hormone-2 receptor selective ligand in the hypothalamus. Endocrin 138(2): p. 831-834.
  • 47. Usdin TB, Modi W, Bonner TI (1996) Assignment of the human PTH2 receptor gene (PTHR2) to chromosome 2q33 by fluorescence in situ hybridization. Genomics 37(1): p. 140-141.
  • 48. Gardella TJ, Vilardaga JP (2015) International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors-family B G protein-coupled receptors. Pharmacol Rev 67(2): p. 310-337.
  • 49. Dobolyi A, Palkovits M, Usdin TB (2003) Expression and distribution of tuberoinfundibular peptide of 39 residues in the rat central nervous system. J Comp Neurol 455(4): p. 547-566.
  • 50. Dobolyi A, Dimitiov E, Palkovits M, et al. (2012) The neuroendocrine functions of the parathyroid hormone 2 receptor. Front Endocrinol (Lausanne) 3: p. 121.
  • 51. Hoare SR, Rubin DA, Jüppner H, et al. (2000) Evaluating the ligand specificity of zebrafish parathyroid hormone (PTH) receptors: comparison of PTH, PTH-related protein, and tuberoinfundibular peptide of 39 residues. Endocrin 141(9): p. 3080-3086.
  • 52. Eichinger A (2002) Transcript expression of the tuberoinfundibular peptide (TIP)39/PTH2 receptor system and non-PTH1 receptor-mediated tonic effects of TIP39 and other PTH2 receptor ligands in renal vessels. Endocrin 143(8): p. 3036-3043.
  • 53. Pinheiro PL, Cardoso JCR, Power DM, et al. (2012) Functional characterization and evolution of PTH/PTHrP receptors: insights from the chicken. BMC Evol Biol 12: p. 110.
  • 54. Rubin DA, Juppner H (1999) Zebrafish express the common parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) and a novel receptor (PTH3R) that is preferentially activated by mammalian and fugufish parathyroid hormone-related peptide. J Biol Chem 274(40): p. 28185-28190.
  • 55. Rubin DA, Hellman P, Zon LI, et al. (1999) A G protein-coupled receptor from zebrafish is activated by human parathyroid hormone and not by human or teleost parathyroid hormone-related peptide. Implications for the evolutionary conservation of calcium-regulating peptide hormones. J Biol Chem 274(33): p. 23035-23042.
  • 56. Rotllant J, Redruello B, Power DM, et al. (2006) Ligand binding and signalling pathways of PTH receptors in sea bream (Sparus auratus) enterocytes. Cell Tissue Res 323(2): p. 333-341.
  • 57. Pinheiro PL, Gomes AS, Power DM, et al. (2010) Gene structure, transcripts and calciotropic effects of the PTH family of peptides in Xenopus and chicken. BMC Evol Biol 10: p. 373.
  • 58. Canario AV, Rotllant J, Power DM, et al. (2006) Novel bioactive parathyroid hormone and related peptides in teleost fish. FEBS Lett 580(1): p. 291-299.
  • 59. Cardoso JC, Felix RC, Power DM (2014) Nematode and arthropod genomes provide new insights into the evolution of class 2 B1 GPCRs. PLoS One 9(3): p. e92220.
  • 60. D'Souza DG, Rana K, Milley KM, et al. (2013) Expression of Wnt signaling skeletal development genes in the cartilaginous fish, elephant shark (Callorhinchus milii). Gen Comp Endocrin 193: p. 1-9.
  • 61. Hwang JI, Moon MJ, Park M, et al. (2013) Expansion of secretin-like G protein-coupled receptors and their peptide ligands via local duplications before and after two rounds of whole-genome duplication. Mol Biol Evo 30(5): p. 1119-1130.
  • 62. On JS, Duan C, Chow BK, et al. (2015) Functional Pairing of Class B1 Ligand-GPCR in Cephalochordate Provides Evidence of the Origin of PTH and PACAP/Glucagon Receptor Family. Mol Biol Evol
  • 63. Cardoso JC, Pinto1 VC, Vieira1 FA, et al. (2006) Evolution of secretin family GPCR members in the metazoa. BMC Evol Biol 6: p. 108.
  • 64. Mirabeau O, Joly JS (2013) Molecular evolution of peptidergic signaling systems in bilaterians. Proc Natl Acad Sci USA 110(22): p. E2028-2037.
  • 65. Liu Y, Ibrahim AS, Walker TI, et al. (2010) Parathyroid hormone gene family in a cartilaginous fish, the elephant shark (Callorhinchus milii). J Bone Miner Res 25(12): p. 2613-2623.
  • 66. Ingleton PM (2002) Parathyroid hormone-related protein in lower vertebrates. Comp Biochem Physiol B Biochem Mol Biol 132(1): p. 87-95.
  • 67. Ingleton PM, Danks JA (1996) Distribution and functions of parathyroid hormone-related protein in vertebrate cells. Int Rev Cytol 166: p. 231-280.
  • 68. Abbink W, Flik G (2007) Parathyroid hormone-related protein in teleost fish. Gen Comp Endocrinol 152(2-3): p. 243-251.
  • 69. Barden JA, Cuthbertson RM (1993) Stabilized NMR structure of human parathyroid hormone(1-34). Eur J Biochem 215(2): p. 315-321.
  • 70. Ray FR, Barden JA, Kemp BE (1993) NMR solution structure of the [Ala26] parathyroid-hormone-related protein(1-34) expressed in humoral hypercalcemia of malignancy. Eur J Biochem 211(1-2): p. 205-211.
  • 71. Shimizu N, Petroni BD, Khatri A, et al. (2003) Functional evidence for an intramolecular side chain interaction between residues 6 and 10 of receptor-bound parathyroid hormone analogues. Biochem 42(8): p. 2282-2290.
  • 72. Blind E, Raue F, Knappe F, et al. (1993) Cyclic AMP formation in rat bone and kidney cells is stimulated equally by parathyroid hormone-related protein (PTHrP) 1-34 and PTH 1-34. Exp Clin Endocrinol 101(3): p. 150-155.
  • 73. Neer RM, Arnaud CD, Zanchetta JR, et al. (2001) Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344(19): p. 1434-1441.
  • 74. Nutt RF, Caulfield MP, Levy JJ, et al. (1990) Removal of partial agonism from parathyroid hormone (PTH)-related protein-(7-34)NH2 by substitution of PTH amino acids at positions 10 and 11. Endocrin 127(1): p. 491-493.
  • 75. Carter PH, Dean T, Gardella TJ, et al. (2015) Actions of the small molecule ligands SW106 and AH-3960 on the type-1 parathyroid hormone receptor. Mol Endocrinol. 29(2): p. 307-321.
  • 76. Mann R, Wigglesworth MJ, Donnelly D (2008) Ligand-receptor interactions at the parathyroid hormone receptors: subtype binding selectivity is mediated via an interaction between residue 23 on the ligand and residue 41 on the receptor. Mol Pharmacol 74(3): p. 605-613.
  • 77. Pioszak AA, Xu HE (2008) Molecular recognition of parathyroid hormone by its G protein-coupled receptor. Proc Natl Acad Sci USA 105(13): p. 5034-5039.
  • 78. Barbier JR, MacLean S, Whitfield JF, et al. (2001) Structural requirements for conserved arginine of parathyroid hormone. Biochemistry 40(30): p. 8955-8961.
  • 79. Dean T, Khatri A, Gardella TJ, et al. (2006) Role of amino acid side chains in region 17-31 of parathyroid hormone (PTH) in binding to the PTH receptor. J Biol Chem 281(43): p. 32485-32495.
  • 80. Weaver RE, Wigglesworth MJ, Donnelly D (2014) A salt bridge between Arg-20 on parathyroid hormone (PTH) and Asp-137 on the PTH1 receptor is essential for full affinity. Peptides 61: p. 83-87.
  • 81. Pizurki L, Rizzoli R, Bonjour JP (1990) Inhibition by (D-Trp12,Tyr34)bPTH(7-34)amide of PTH and PTHrP effects on Pi transport in renal cells. Am J Physiol 259(2 Pt 2): p. F389-392.
  • 82. Carter PH, Juppner H, Gardella TJ (1999) Studies of the N-terminal region of a parathyroid hormone-related peptide (1-36) analog: receptor subtype-selective agonists, antagonists, and photochemical cross-linking agents. Endocrin 140(11): p. 4972-4981.
  • 83. Cohen FE, Strewler GJ, Bradley MS, et al. (1991) Analogues of parathyroid hormone modified at positions 3 and 6. Effects on receptor binding and activation of adenylyl cyclase in kidney and bone. J Biol Chem 266(3): p. 1997-2004.
  • 84. Whitfield JF, Morley P (1995) Small bone-building fragments of parathyroid hormone: new therapeutic agents for osteoporosis. Trends Pharmacol Sci 16(11): p. 382-386.
  • 85. Whitfield JF, Bringhurst FR (2000) Lactam formation increases receptor binding, adenylyl cyclase stimulation and bone growth stimulation by human parathyroid hormone (hPTH)(1-28)NH2. J Bone Miner Res 15(5): p. 964-970.
  • 86. Luck MD, Carter PH, Gardella TJ (1999) The (1-14) fragment of parathyroid hormone (PTH) activates intact and amino-terminally truncated PTH-1 receptors. Mol Endocrinol 13(5): p. 670-680.
  • 87. Shimizu M, Potts JT, Gardella TJ, et al. (2000) Minimization of parathyroid hormone. Novel amino-terminal parathyroid hormone fragments with enhanced potency in activating the type-1 parathyroid hormone receptor. J Biol Chem 275(29): p. 21836-21843.
  • 88. Liu Y, Cai Y, Liu W, et al. (2015) Triblock peptide-linker-lipid molecular design improves potency of peptide ligands targeting family B G protein-coupled receptors. Chem Commun (Camb) 51(28): p. 6157-6160.
  • 89. Neer M, Slovik DM, DalyM, et al. (1993) Treatment of postmenopausal osteoporosis with daily parathyroid hormone plus calcitriol. Osteoporos Int 3 Suppl 1: p. 204-205.
  • 90. Reeve J, Hesp R, Williams D, et al. (1976) Anabolic effect of low doses of a fragment of human parathyroid hormone on the skeleton in postmenopausal osteoporosis. Lancet 1(7968): p. 1035-1038.
  • 91. Divieti P, Geller AI, Suliman G, et al. (2005) Receptors specific for the carboxyl-terminal region of parathyroid hormone on bone-derived cells: determinants of ligand binding and bioactivity. Endocrin 146(4): p. 1863-1870.
  • 92. Inomata N, Akiyama M, Kubota N, et al. (1995) Characterization of a novel parathyroid hormone (PTH) receptor with specificity for the carboxyl-terminal region of PTH-(1-84). Endocrin 136(11): p. 4732-4740.
  • 93. Venkatesh B, Lee AP, Ravi V, et al. (2014) Elephant shark genome provides unique insights into gnathostome evolution. Nature 505(7482): p. 174-179.


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