Control of Parathyroid Hormone Secretion by Extracellular Ca2+

  • Edward M. BrownEmail author


Parathyroid hormone (PTH) plays critical roles in maintaining the nearly constant level of the extracellular ionized calcium concentration (Ca2+ o) that is required for the well-being of complex organisms, including humans. Therefore, an understanding of the factors controlling PTH secretion and the mechanisms by which they do so is essential for a thorough comprehension of this regulatory system. The discussion that follows covers the overall control of PTH secretion by changes in the extracellular calcium concentration (Ca2+ o) by virtue of its regulation of the secretion of preformed hormonal stores, hormonal degradation, biosynthesis of PTH, and parathyroid cellular proliferation. Phosphate, 1,25(OH) 2D3, and fibroblast growth factor (FGF23) also regulate parathyroid function, stimulating it in the case of phosphate and inhibiting it in the case of 1,25(OH)2D3 and FGF23. The regulatory roles of these three factors are covered in Chaps. 6 and 8 and will only be alluded to briefly here.


Parathyroid hormone (PTH) Parathyroid cell Calcium-sensing receptor (CaSR) Calcium (Ca2+Phosphate 1,25-dihydroxyvitamin D [1,25(OH)2D3Fibroblast growth factor 23 (FGF23) 


  1. 1.
    Hu MC, Shiizaki K, Kuro-o M, Moe OW (2013) Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 75:503–533CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Brown AJ, Slatopolsky E (2007) Drug insight: vitamin D analogs in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Nat Clin Pract Endocrinol Metab 3:134–144CrossRefPubMedGoogle Scholar
  3. 3.
    Naveh-Many T, Nechama M (2007) Regulation of parathyroid hormone mRNA stability by calcium, phosphate and uremia. Curr Opin Nephrol Hypertens 16:305–310CrossRefPubMedGoogle Scholar
  4. 4.
    Silver J, Rodriguez M, Slatopolsky E (2012) FGF23 and PTH–double agents at the heart of CKD. Nephrol Dial Transplant 27:1715–1720CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Shoback D (2008) Clinical practice. Hypoparathyroidism. N Engl J Med 359:391–403CrossRefPubMedGoogle Scholar
  6. 6.
    Brown EM (2007) Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab 3:122–133CrossRefPubMedGoogle Scholar
  7. 7.
    Brown EM (1991) Extracellular Ca2+ sensing, regulation of parathyroid cell function, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev 71:371–411PubMedGoogle Scholar
  8. 8.
    Bringhurst FR, Demay MB, Kronenberg HM (1998) Hormones and disorders of mineral metabolism. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds) Williams textbook of endocrinology. W.B. Saunders, Philadelphia, pp 1155–1209Google Scholar
  9. 9.
    Huan J, Martuseviciene G, Olgaard K, Lewin E (2007) Calcium-sensing receptor and recovery from hypocalcaemia in thyroparathyroidectomized rats. Eur J Clin Invest 37:214–221CrossRefPubMedGoogle Scholar
  10. 10.
    Neuman WF (1982) Blood: bone equilibrium. Calcif Tissue Int 34:117–120CrossRefPubMedGoogle Scholar
  11. 11.
    Ward BK, Magno AL, Walsh JP, Ratajczak T (2012) The role of the calcium-sensing receptor in human disease. Clin Biochem 45:943–953CrossRefPubMedGoogle Scholar
  12. 12.
    Schwarz P, Sorensen HA, McNair P, Transbol I (1993) Cica-clamp technique: a method for quantifying parathyroid hormone secretion: a sequential citrate and calcium clamp study. Eur J Clin Invest 23:546–553CrossRefPubMedGoogle Scholar
  13. 13.
    Jung A, Mayer GP, Hurst JG, Neer R, Potts JT Jr (1982) Model for parathyroid hormone secretion and metabolism in calves. Am J Physiol 242:R141–R150PubMedGoogle Scholar
  14. 14.
    Huang Y, Zhou Y, Yang W, Butters R, Lee HW, Li S, Castiblanco A, Brown EM, Yang JJ (2007) Identification and dissection of Ca(2+)-binding sites in the extracellular domain of Ca(2+)-sensing receptor. J Biol Chem 282:19000–19010Google Scholar
  15. 15.
    Morrissey JJ, Hamilton JW, MacGregor RR, Cohn DV (1980) The secretion of parathormone fragments 34–84 and 37–84 by dispersed porcine parathyroid cells. Endocrinology 107:164–171CrossRefPubMedGoogle Scholar
  16. 16.
    Brown EM, Leombruno R, Thatcher J, Burrowes M (1985) The acute secretory response to alterations in the extracellular calcium concentration and dopamine in perifused bovine parathyroid cells. Endocrinology 116:1123–1132CrossRefPubMedGoogle Scholar
  17. 17.
    Morrissey JJ, Cohn DV (1979) Regulation of secretion of parathormone and secretory protein protein-I from separate intracellular pools by calcium, dibutyryl cyclic AMP, and (l)-isoproterenol. J Cell Biol 82:93–102CrossRefPubMedGoogle Scholar
  18. 18.
    Morrissey JJ, Cohn DV (1979) Secretion and degradation of parathormone as a function of intracellular maturation of hormone pools. Modulation by calcium and dibutyryl cyclic AMP. J Cell Biol 83:521–528CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Naveh-Many T, Friedlaender MM, Mayer H, Silver J (1989) Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat. Dominant role of 1,25-dihydroxyvitamin D. Endocrinology 125:275–280CrossRefPubMedGoogle Scholar
  20. 20.
    Denda M, Finch J, Slatopolsky E (1996) Phosphorus accelerates the development of parathyroid hyperplasia and secondary hyperparathyroidism in rats with renal failure. Am J Kidney Dis 28:596–602CrossRefPubMedGoogle Scholar
  21. 21.
    Goodman WG, Quarles LD (2008) Development and progression of secondary hyperparathyroidism in chronic kidney disease: lessons from molecular genetics. Kidney Int 74:276–288CrossRefPubMedGoogle Scholar
  22. 22.
    Schaffler MB, Cheung WY, Majeska R, Kennedy O (2014) Osteocytes: master orchestrators of bone. Calcif Tissue Int 94:5–24CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Demay MB (2013) Physiological insights from the vitamin D receptor knockout mouse. Calcif Tissue Int 92:99–105CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Silver J, Naveh-Many T (2009) Phosphate and the parathyroid. Kidney Int 75:898–905CrossRefPubMedGoogle Scholar
  25. 25.
    Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T (2010) PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol 299:F882–F889CrossRefPubMedGoogle Scholar
  26. 26.
    Habener JF, Amherdt M, Ravazzola M, Orci L (1979) Parathyroid hormone biosynthesis. Correlation of conversion of biosynthetic precursors with intracellular protein migration as determined by electron microscope autoradiography. J Cell Biol 80:715–731CrossRefPubMedGoogle Scholar
  27. 27.
    Morrissey JJ, Cohn DV (1978) The effects of calcium and magnesium on the secretion of parathormone and parathyroid secretory protein by isolated porcine parathyroid cells. Endocrinology 103:2081–2090CrossRefPubMedGoogle Scholar
  28. 28.
    Brown EM, Hurwitz S, Aurbach GD (1976) Preparation of viable isolated bovine parathyroid cells. Endocrinology 99:1582–1588CrossRefPubMedGoogle Scholar
  29. 29.
    Brown EM, Gardner DG, Windeck RA, Hurwitz S, Brennan MF, Aurbach GD (1979) ß-adrenergically stimulated adenosine 3′,5′-monophosphate accumulation in and parathyroid hormone release from dispersed human parathyroid cells. J Clin Endocrinol Metab 48:618–626CrossRefPubMedGoogle Scholar
  30. 30.
    Schwarz P (1993) Dose response dependency in regulation of acute S-PTH(1–84) release in normal humans: a citrate and calcium infusion study. Scand J Clin Lab Invest 53:601–605CrossRefPubMedGoogle Scholar
  31. 31.
    Brown EM (1983) Four parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 56:572–581CrossRefPubMedGoogle Scholar
  32. 32.
    Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H 3rd, Thakker RV (2013) Mutations affecting G-protein subunit alpha11 in hypercalcemia and hypocalcemia. N Engl J Med 368:2476–2486CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Brown EM, MacLeod RJ (2001) Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 81:239–297PubMedGoogle Scholar
  34. 34.
    Magno AL, Ward BK, Ratajczak T (2011) The calcium-sensing receptor: a molecular perspective. Endocr Rev 32:3–30CrossRefPubMedGoogle Scholar
  35. 35.
    Conigrave AD, Ward DT (2013) Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract Res Clin Endocrinol Metab 27:315–331CrossRefPubMedGoogle Scholar
  36. 36.
    Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC (1993) Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 366:575–580CrossRefPubMedGoogle Scholar
  37. 37.
    Nemeth E, Scarpa A (1987) Rapid mobilization of cellular Ca2+ in bovine parathyroid cells by external divalent cations. J Biol Chem 202:5188–5196Google Scholar
  38. 38.
    Shoback DM, Chen TH, Lattyak B, King K, Johnson RM (1993) Effects of high extracellular calcium and strontium on inositol polyphosphates in bovine parathyroid cells. J Bone Miner Res 8:891–898CrossRefPubMedGoogle Scholar
  39. 39.
    Chakravarti B, Chattopadhyay N, Brown EM (2012) Signaling through the extracellular calcium-sensing receptor (CaSR). Adv Exp Med Biol 740:103–142CrossRefPubMedGoogle Scholar
  40. 40.
    Chen C, Barnett J, Congo D, Brown E (1989) Divalent cations suppress 3′,5′-adenosine monophosphate accumulation by stimulating a pertussis toxin-sensitive guanine nucleotide-binding protein in cultured bovine parathyroid cells. Endocrinology 124:233–239CrossRefPubMedGoogle Scholar
  41. 41.
    Brauner-Osborne H, Wellendorph P, Jensen AA (2007) Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Curr Drug Targets 8:169–184CrossRefPubMedGoogle Scholar
  42. 42.
    Garrett JE, Capuano IV, Hammerland LG, Hung BC, Brown EM, Hebert SC, Nemeth EF, Fuller F (1995) Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs. J Biol Chem 270:12919–12925CrossRefPubMedGoogle Scholar
  43. 43.
    Fan GF, Ray K, Zhao XM, Goldsmith PK, Spiegel AM (1998) Mutational analysis of the cysteines in the extracellular domain of the human Ca2+ receptor: effects on cell surface expression, dimerization and signal transduction. FEBS Lett 436:353–356CrossRefPubMedGoogle Scholar
  44. 44.
    Pidasheva S, Grant M, Canaff L, Ercan O, Kumar U, Hendy GN (2006) Calcium-sensing receptor dimerizes in the endoplasmic reticulum: biochemical and biophysical characterization of CASR mutants retained intracellularly. Hum Mol Genet 15:2200–2209CrossRefPubMedGoogle Scholar
  45. 45.
    Grant MP, Stepanchick A, Cavanaugh A, Breitwieser GE (2011) Agonist-driven maturation and plasma membrane insertion of calcium-sensing receptors dynamically control signal amplitude. Sci Signal 4:ra78CrossRefPubMedGoogle Scholar
  46. 46.
    Nesbit MA, Hannan FM, Howles SA, Reed AA, Cranston T, Thakker CE, Gregory L, Rimmer AJ, Rust N, Graham U, Morrison PJ, Hunter SJ, Whyte MP, McVean G, Buck D, Thakker RV (2013) Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet 45:93–97CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Hu J, Spiegel AM (2003) Naturally occurring mutations in the extracellular Ca2 + −sensing receptor: implications for its structure and function. Trends Endocrinol Metab 14:282–288CrossRefPubMedGoogle Scholar
  48. 48.
    Huang Y, Zhou Y, Castiblanco A, Yang W, Brown EM, Yang JJ (2009) Multiple Ca(2+)-binding sites in the extracellular domain of the Ca(2+)-sensing receptor corresponding to cooperative Ca(2+) response. Biochemistry 48:388–398CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    Silve C, Petrel C, Leroy C, Bruel H, Mallet E, Rognan D, Ruat M (2005) Delineating a Ca2+ binding pocket within the venus flytrap module of the human calcium-sensing receptor. J Biol Chem 280:37917–37923CrossRefPubMedGoogle Scholar
  50. 50.
    Geibel J, Sritharan K, Geibel R, Geibel P, Persing JS, Seeger A, Roepke TK, Deichstetter M, Prinz C, Cheng SX, Martin D, Hebert SC (2006) Calcium-sensing receptor abrogates secretagogue- induced increases in intestinal net fluid secretion by enhancing cyclic nucleotide destruction. Proc Natl Acad Sci U S A 103:9390–9397CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    Fox J, Lowe SH, Petty BA, Nemeth EF (1999) NPS R-568: a type II calcimimetic compound that acts on parathyroid cell calcium receptor of rats to reduce plasma levels of parathyroid hormone and calcium. J Pharmacol Exp Ther 290:473–479PubMedGoogle Scholar
  52. 52.
    Nemeth EF, Steffey ME, Hammerland LG, Hung BC, Van Wagenen BC, DelMar EG, Balandrin MF (1998) Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci U S A 95:4040–4045CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Huang Y, Breitwieser GE (2007) Rescue of calcium-sensing receptor mutants by allosteric modulators reveals a conformational checkpoint in receptor biogenesis. J Biol Chem 282:9517–9525CrossRefPubMedGoogle Scholar
  54. 54.
    Leach K, Wen A, Cook AE, Sexton PM, Conigrave AD, Christopoulos A (2013) Impact of clinically relevant mutations on the pharmacoregulation and signaling bias of the calcium-sensing receptor by positive and negative allosteric modulators. Endocrinology 154:1105–1116CrossRefPubMedGoogle Scholar
  55. 55.
    Brown EM (2010) Clinical utility of calcimimetics targeting the extracellular calcium-sensing receptor (CaSR). Biochem Pharmacol 80:297–307CrossRefPubMedGoogle Scholar
  56. 56.
    Nemeth EF, Shoback D (2013) Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders. Best Pract Res Clin Endocrinol Metab 27:373–384CrossRefPubMedGoogle Scholar
  57. 57.
    Ho C, Conner DA, Pollak MR, Ladd DJ, Kifor O, Warren HB, Brown EM, Seidman JG, Seidman CE (1995) A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism [see comments]. Nat Genet 11:389–394CrossRefPubMedGoogle Scholar
  58. 58.
    Chang W, Tu C, Chen T, Liu B, Elalieh H, Dvorak M, Clemens T, Kream B, Halloran B, Bikle D, Shoback D (2007) Conditional knockouts in early and mature osteoblasts reveals a critical role for Ca2+ receptors in bone development. J Bone Miner Res 22:S79, Abst 1284Google Scholar
  59. 59.
    Wettschureck N, Lee E, Libutti SK, Offermanns S, Robey PG, Spiegel AM (2007) Parathyroid-specific double knockout of Gq and G11 alpha-subunits leads to a phenotype resembling germline knockout of the extracellular Ca2 ± sensing receptor. Mol Endocrinol 21:274–280CrossRefPubMedGoogle Scholar
  60. 60.
    Bourdeau A, Souberbielle J-C, Bonnet P, Herviaux P, Sachs C, Lieberherr M (1992) Phospholipase-A2 action and arachidonic acid metabolism in calcium-mediated parathyroid hormone secretion. Endocrinology 130:1339–1344PubMedGoogle Scholar
  61. 61.
    Bourdeau A, Moutahir M, Souberbielle JC, Bonnet P, Herviaux P, Sachs C, Lieberherr M (1994) Effects of lipoxygenase products of arachidonate metabolism on parathyroid hormone secretion. Endocrinology 135:1109–1112PubMedGoogle Scholar
  62. 62.
    Corbetta S, Lania A, Filopanti M, Vincentini L, Ballare E, Spada A (2002) Mitogen-activated protein kinase cascade in human normal and tumoral parathyroid cells. J Clin Endocrinol Metab 87:2201–2205CrossRefPubMedGoogle Scholar
  63. 63.
    Lu M, Forsberg L, Hoog A, Juhlin CC, Vukojevic V, Larsson C, Conigrave AD, Delbridge LW, Gill A, Bark C, Farnebo LO, Branstrom R (2008) Heterogeneous expression of SNARE proteins SNAP-23, SNAP-25, Syntaxin1 and VAMP in human parathyroid tissue. Mol Cell Endocrinol 287:72–80CrossRefPubMedGoogle Scholar
  64. 64.
    Quinn SJ, Kifor O, Kifor I, Butters RR Jr, Brown EM (2007) Role of the cytoskeleton in extracellular calcium-regulated PTH release. Biochem Biophys Res Commun 354:8–13CrossRefPubMedGoogle Scholar
  65. 65.
    Mendoza FJ, Lopez I, Canalejo R, Almaden Y, Martin D, Aguilera-Tejero E, Rodriguez M (2009) Direct upregulation of parathyroid calcium-sensing receptor and vitamin D receptor by calcimimetics in uremic rats. Am J Physiol Renal Physiol 296:F605–F613CrossRefPubMedGoogle Scholar
  66. 66.
    Nielsen PK, Rasmussen AK, Butters R, Feldt-Rasmussen U, Bendtzen K, Diaz R, Brown EM, Olgaard K (1997) Inhibition of PTH secretion by interleukin-1 beta in bovine parathyroid glands in vitro is associated with an up-regulation of the calcium- sensing receptor mRNA. Biochem Biophys Res Commun 238:880–885CrossRefPubMedGoogle Scholar
  67. 67.
    Canaff L, Zhou X, Hendy GN (2008) The proinflammatory cytokine, interleukin-6, up-regulates calcium-sensing receptor gene transcription via Stat1/3 and Sp1/3. J Biol Chem 283:13586–13600CrossRefPubMedGoogle Scholar
  68. 68.
    Murphey ED, Chattopadhyay N, Bai M, Kifor O, Harper D, Traber DL, Hawkins HK, Brown EM, Klein GL (2000) Up-regulation of the parathyroid calcium-sensing receptor after burn injury in sheep: a potential contributory factor to postburn hypocalcemia. Crit Care Med 28:3885–3890CrossRefPubMedGoogle Scholar
  69. 69.
    Maiti A, Beckman MJ (2007) Extracellular calcium is a direct effecter of VDR levels in proximal tubule epithelial cells that counter-balances effects of PTH on renal Vitamin D metabolism. J Steroid Biochem Mol Biol 103:504–508CrossRefPubMedGoogle Scholar
  70. 70.
    Cholst I, Steinberg S, Tropper P, Fox H, Segre G (1984) The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 310:1221–1225CrossRefPubMedGoogle Scholar
  71. 71.
    Conigrave AD, Mun HC, Lok HC (2007) Aromatic l-amino acids activate the calcium-sensing receptor. J Nutr 137:1524S–1527S; discussion 1548SPubMedGoogle Scholar
  72. 72.
    Conigrave AD, Mun HC, Brennan SC (2007) Physiological significance of l-amino acid sensing by extracellular Ca(2+)-sensing receptors. Biochem Soc Trans 35:1195–1198CrossRefPubMedGoogle Scholar
  73. 73.
    Hira T, Nakajima S, Eto Y, Hara H (2008) Calcium-sensing receptor mediates phenylalanine-induced cholecystokinin secretion in enteroendocrine STC-1 cells. FEBS J 275:4620–4626CrossRefPubMedGoogle Scholar
  74. 74.
    D’Amour P (2006) Circulating PTH molecular forms: what we know and what we don’t. Kidney Int Suppl 102:S29–33Google Scholar
  75. 75.
    Mayer GP, Keaton JA, Hurst JG, Habener JF (1979) Effects of plasma calcium concentration on the relative proportion of hormone and carboxyl fragments in parathyroid venous blood. Endocrinology 104:1778–1784CrossRefPubMedGoogle Scholar
  76. 76.
    Hanley D, Takatsuki K, Sultan J, Schneider A, Sherwood L (1978) Direct release of parathyroid hormone fragments from functioning bovine parathyroid glands in vitro. J Clin Invest 62:1247–1254CrossRefPubMedCentralPubMedGoogle Scholar
  77. 77.
    Segre GV, Niall HD, Sauer RT, Potts JT Jr (1977) Edman degradation of radioiodinated parathyroid hormone: application to sequence analysis and hormone metabolism in vivo. Biochemistry 16:2417–2427CrossRefPubMedGoogle Scholar
  78. 78.
    D’Amour P, Rakel A, Brossard JH, Rousseau L, Albert C, Cantor T (2006) Acute regulation of circulating parathyroid hormone (PTH) molecular forms by calcium: utility of PTH fragments/PTH(1–84) ratios derived from three generations of PTH assays. J Clin Endocrinol Metab 91:283–289CrossRefPubMedGoogle Scholar
  79. 79.
    Nussbaum SR, Potts J Jr, Wang CA, Zahradnik R, Lavigne JR, Kim L, Segre GV (1987) A highly sensitive two-site immunoradiometric assay for parathyroid hormone (PTH) and its clinical utility in the evaluation of patients with hypercalcemia. Clin Chem 33:1364–1367PubMedGoogle Scholar
  80. 80.
    Gao P, Scheibel S, D’Amour P, John MR, Rao SD, Schmidt-Gayk H, Cantor TL (2001) Development of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone 1–84: implications for improvement of accurate assessment of parathyroid function. J Bone Miner Res 16:605–614CrossRefPubMedGoogle Scholar
  81. 81.
    Friedman PA, Goodman WG (2006) PTH(1–84)/PTH(7–84): a balance of power. Am J Physiol Renal Physiol 290:F975–F984CrossRefPubMedGoogle Scholar
  82. 82.
    Schwarz P, Sorensen HA, Transbol I, McNair P (1992) Regulation of acute parathyroid hormone release in normal humans: combined calcium and citrate clamp study. Am J Physiol 263:E195–E198PubMedGoogle Scholar
  83. 83.
    Valle C, Rodriguez M, Santamaria R, Almaden Y, Rodriguez ME, Canadillas S, Martin-Malo A, Aljama P (2008) Cinacalcet reduces the set point of the PTH-calcium curve. J Am Soc Nephrol 19:2430–2436CrossRefPubMedCentralPubMedGoogle Scholar
  84. 84.
    Nechama M, Ben-Dov IZ, Silver J, Naveh-Many T (2009) Regulation of PTH mRNA stability by the calcimimetic R568 and the phosphorus binder lanthanum carbonate in CKD. Am J Physiol Renal Physiol 296:F795–F800CrossRefPubMedGoogle Scholar
  85. 85.
    Nechama M, Peng Y, Bell O, Briata P, Gherzi R, Schoenberg DR, Naveh-Many T (2009) KSRP-PMR1-exosome association determines parathyroid hormone mRNA levels and stability in transfected cells. BMC Cell Biol 10:70CrossRefPubMedCentralPubMedGoogle Scholar
  86. 86.
    Levi R, Ben-Dov IZ, Lavi-Moshayoff V, Dinur M, Martin D, Naveh-Many T, Silver J (2006) Increased parathyroid hormone gene expression in secondary hyperparathyroidism of experimental uremia is reversed by calcimimetics: correlation with posttranslational modification of the trans acting factor AUF1. J Am Soc Nephrol 17:107–112CrossRefPubMedGoogle Scholar
  87. 87.
    Raisz L (1965) Regulation by calcium of parathyroid growth and secretion in vitro. Nature 44:103–110Google Scholar
  88. 88.
    Roth SI, Raisz LG (1966) The course and reversibility of the calcium effect on the ultrastructure of the rat parathyroid gland in organ culture. Lab Invest 15:1187–1211PubMedGoogle Scholar
  89. 89.
    Egbuna OI, Brown EM (2008) Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol 22:129–148CrossRefPubMedCentralPubMedGoogle Scholar
  90. 90.
    Wada M, Furuya Y, Sakiyama J-i, Kobayashi N, Miyata S, Ishii H, Hagano N (1997) The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. J Clin Invest 100:2977–2983CrossRefPubMedCentralPubMedGoogle Scholar
  91. 91.
    Finch JL, Lee DH, Liapis H, Ritter C, Zhang S, Suarez E, Ferder L, Slatopolsky E (2013) Phosphate restriction significantly reduces mortality in uremic rats with established vascular calcification. Kidney Int 84:1145–1153CrossRefPubMedGoogle Scholar
  92. 92.
    Arcidiacono MV, Sato T, Alvarez-Hernandez D, Yang J, Tokumoto M, Gonzalez-Suarez I, Lu Y, Tominaga Y, Cannata-Andia J, Slatopolsky E, Dusso AS (2008) EGFR activation increases parathyroid hyperplasia and calcitriol resistance in kidney disease. J Am Soc Nephrol 19:310–320CrossRefPubMedCentralPubMedGoogle Scholar
  93. 93.
    Dusso AS, Pavlopoulos T, Naumovich L, Lu Y, Finch J, Brown AJ, Morrissey J, Slatopolsky E (2001) p21(WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth. Kidney Int 59:855–865CrossRefPubMedGoogle Scholar
  94. 94.
    Gogusev J, Duchambon P, Stoermann-Chopard C, Giovannini M, Sarfati E, Drueke TB (1996) De novo expression of transforming growth factor-alpha in parathyroid gland tissue of patients with primary or secondary uraemic hyperparathyroidism. Nephrol Dial Transplant 11:2155–2162CrossRefPubMedGoogle Scholar
  95. 95.
    Cozzolino M, Lu Y, Sato T, Yang J, Suarez IG, Brancaccio D, Slatopolsky E, Dusso AS (2005) A critical role for enhanced TGF-alpha and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease. Am J Physiol Renal Physiol 289:F1096–F1102CrossRefPubMedGoogle Scholar
  96. 96.
    Lin SY, Makino K, Xia W, Matin A, Wen Y, Kwong KY, Bourguignon L, Hung MC (2001) Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol 3:802–808CrossRefPubMedGoogle Scholar
  97. 97.
    Cozzolino M, Lu Y, Finch J, Slatopolsky E, Dusso AS (2001) p21WAF1 and TGF-alpha mediate parathyroid growth arrest by vitamin D and high calcium. Kidney Int 60:2109–2117CrossRefPubMedGoogle Scholar
  98. 98.
    Kanesaka Y, Tokunaga H, Iwashita K, Fujimura S, Naomi S, Tomita K (2001) Endothelin receptor antagonist prevents parathyroid cell proliferation of low calcium diet-induced hyperparathyroidism in rats. Endocrinology 142:407–413CrossRefPubMedGoogle Scholar
  99. 99.
    Wang Q, Palnitkar S, Parfitt AM (1996) Parathyroid cell proliferation in the rat: effect of age and of phosphate administration and recovery. Endocrinology 137:4558–4562PubMedGoogle Scholar
  100. 100.
    Colloton M, Shatzen E, Miller G, Stehman-Breen C, Wada M, Lacey D, Martin D (2005) Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. Kidney Int 67:467–476CrossRefPubMedGoogle Scholar
  101. 101.
    Mizobuchi M, Ogata H, Hatamura I, Saji F, Koiwa F, Kinugasa E, Koshikawa S, Akizawa T (2007) Activation of calcium-sensing receptor accelerates apoptosis in hyperplastic parathyroid cells. Biochem Biophys Res Commun 362:11–16CrossRefPubMedGoogle Scholar

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© Springer-Verlag Italia 2015

Authors and Affiliations

  1. 1.Division of Endocrinology, Diabetes and Hypertension, Department of MedicineBrigham and Women’s HospitalBostonUSA

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