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The PTH/Vitamin D/FGF23 Axis

  • David GoltzmanEmail author
  • Andrew C. Karaplis
Chapter

Abstract

Calcium and phosphorus are essential for a myriad of intracellular functions and also form the basis for the structural integrity of bone. As such, mechanisms have evolved to ensure exquisite control over their circulating concentrations. These concentrations are largely maintained by fluxes of these mineral ions across the intestine, kidney, and bone and are regulated by three major hormones, parathyroid hormone (PTH), the active form of vitamin D, 1,25-dihydroxyvitamin D, and fibroblast growth factor-23 (FGF23). Each hormone acts to directly influence mineral ion transport across intestine or kidney and may also regulate mineral ion entry into and out of bone. The production and secretion of each hormone may in turn be modulated by circulating concentrations of these mineral ions and by the action of the other hormones, producing a complex network of negative and positive feedback systems. Disruption of these homeostatic systems can produce dramatic disease profiles but improved understanding of the underlying molecular mechanisms may lead to more salutary approaches to therapy.

Keywords

Parathyroid hormone Vitamin D Fibroblast growth factor-23 Calcium Phosphorus Kidney Intestine Bone Ion transport Feedback loops 

References

  1. 1.
    Christakos S (2012) Recent advances in our understanding of 1,25-dihydroxyvitamin D(3) regulation of intestinal calcium absorption. Arch Biochem Biophys 523:73–76CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Forster IC, Hernando N, Biber J, Murer H (2006) Proximal tubular handling of phosphate: A molecular perspective. Kidney Int 70:1548–1559CrossRefPubMedGoogle Scholar
  3. 3.
    Brown EM (2013) Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract Res Clin Endocrinol Metab 27:333–343CrossRefPubMedGoogle Scholar
  4. 4.
    Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM (1992) Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A 89:8097–8101CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Kremer R, Bolivar I, Goltzman D, Hendy GN (1989) Influence of calcium and 1,25-dihydroxycholecalciferol on proliferation and proto-oncogene expression in primary cultures of bovine parathyroid cells. Endocrinology 125:935–941CrossRefPubMedGoogle Scholar
  6. 6.
    Panda DK, Miao D, Bolivar I et al (2004) Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem 279:16754–16766CrossRefPubMedGoogle Scholar
  7. 7.
    Tregear GW, Van Rietschoten J, Greene E et al (1973) Bovine parathyroid hormone: minimum chain length of synthetic peptide required for biological activity. Endocrinology 93:1349–1353CrossRefPubMedGoogle Scholar
  8. 8.
    Goltzman D, Peytremann A, Callahan E et al (1975) Analysis of the requirements for parathyroid hormone action in renal membranes with the use of inhibiting analogues. J Biol Chem 250:3199–3203PubMedGoogle Scholar
  9. 9.
    Jüppner H, Abou-Samra AB, Freeman M et al (1991) A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254:1024CrossRefPubMedGoogle Scholar
  10. 10.
    Abou-Samra AB, Jüppner H, Force T et al (1992) Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci U S A 89:2732–2736CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Lambers TT, Bindels RJ, Hoenderop JG (2006) Coordinated control of renal Ca2+ handling. Kidney Int 69:650–654CrossRefPubMedGoogle Scholar
  12. 12.
    van Abel M, Hoenderop JG, van der Kemp AW et al (2005) Coordinated control of renal Ca(2+) transport proteins by parathyroid hormone. Kidney Int 68:1708–1721CrossRefPubMedGoogle Scholar
  13. 13.
    Cha SK, Wu T, Huang CL (2008) Protein kinase C inhibits caveolae-mediated endocytosis of TRPV5. Am J Physiol Renal Physiol 294:F1212–F1221CrossRefPubMedGoogle Scholar
  14. 14.
    Topala CN, Schoeber JP, Searchfield LE et al (2009) Activation of the Ca(2+)-sensing receptor stimulates the activity of the epithelial Ca(2+) channel TRPV5. Cell Calcium 45:331–339CrossRefPubMedGoogle Scholar
  15. 15.
    Custer M, Lotscher M, Biber J et al (1994) Expression of Na-P(i) cotransport in rat kidney: localization by RT-PCR and immunohistochemistry. Am J Physiol 266:F767–F774PubMedGoogle Scholar
  16. 16.
    Bacic D, Lehir M, Biber J et al (2006) The renal Na+/phosphate cotransporter NaPi-IIa is internalized via the receptor-mediated endocytic route in response to parathyroid hormone. Kidney Int 69:495–503CrossRefPubMedGoogle Scholar
  17. 17.
    Segawa H, Yamanaka S, Onitsuka A et al (2007) Parathyroid hormone-dependent endocytosis of renal type IIc Na-Pi cotransporter. Am J Physiol Renal Physiol 292:F395–F403CrossRefPubMedGoogle Scholar
  18. 18.
    Traebert M, Volkl H, Biber J et al (2000) Luminal and contraluminal action of 1–34 and 3–34 PTH peptides on renal type IIa Na-P(i) cotransporter. Am J Physiol Renal Physiol 278:F792–F798PubMedGoogle Scholar
  19. 19.
    Brenza HL, Kimmel-Jehan C, Jehan F et al (1998) Parathyroid hormone activation of the 25-hydroxyvitamin D3-1alpha-hydroxylase gene promoter. Proc Natl Acad Sci U S A 95:1387–1391CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Rouleau MF, Mitchell J, Goltzman D (1990) Characterization of the major parathyroid hormone target cell in the endosteal metaphysis of rat long bones. J Bone Miner Res 5:1043–1053CrossRefPubMedGoogle Scholar
  21. 21.
    Miao D, He B, Karaplis AC, Goltzman D (2002) Parathyroid hormone is essential for normal fetal bone formation. J Clin Invest 109:1173–1182CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342CrossRefPubMedGoogle Scholar
  23. 23.
    Silva BC, Costa AG, Cusano NE et al (2011) Catabolic and anabolic actions of parathyroid hormone on the skeleton. J Endocrinol Invest 34:801–810PubMedCentralPubMedGoogle Scholar
  24. 24.
    MacLaughlin JA, Anderson RR, Holick MF (1982) Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin. Science 216:1001–1003CrossRefPubMedGoogle Scholar
  25. 25.
    Dastani Z, Berger C, Langsetmo L et al (2014) In healthy adults, biological activity of vitamin D, as assessed by serum PTH, is largely independent of DBP concentrations. J Bone Miner Res 29:494–499CrossRefPubMedGoogle Scholar
  26. 26.
    Zhu JG, Ochalek JT, Kaufmann M et al (2013) CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. Proc Natl Acad Sci U S A 110:15650–15655CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Jones G, Strugnell SA, DeLuca HF (1998) Current understanding of the molecular actions of vitamin D. Physiol Rev 78:1193–1231PubMedGoogle Scholar
  28. 28.
    Murayama A, Takeyama K, Kitanaka S et al (1999) Positive and negative regulations of the renal 25-hydroxyvitamin D3 1alpha-hydroxylase gene by parathyroid hormone, calcitonin, and 1alpha,25(OH)2D3 in intact animals. Endocrinology 140:2224–2231PubMedGoogle Scholar
  29. 29.
    Liu P, Stenger S, Li H et al (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311:1770–1773CrossRefPubMedGoogle Scholar
  30. 30.
    St-Arnaud R (2010) CYP24A1-deficient mice as a tool to uncover a biological activity for vitamin D metabolites hydroxylated at position 24. J Steroid Biochem Mol Biol 121:254–256CrossRefPubMedGoogle Scholar
  31. 31.
    Shimada T, Hasegawa H, Yamazaki Y et al (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435CrossRefPubMedGoogle Scholar
  32. 32.
    Pike JW, Meyer MB (2014) Fundamentals of vitamin D hormone-regulated gene expression. J Steroid Biochem Mol Biol 144PA:5–11. pii: S0960-0760(13)00234-3. doi: 10.1016/j.jsbmb.2013.11.004. PMID: 24239506
  33. 33.
    Meyer MB, Watanuki M, Kim S et al (2006) The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells. Mol Endocrinol 20:1447–1461CrossRefPubMedGoogle Scholar
  34. 34.
    Fleet JC, Wood RJ (1994) Identification of calbindin D-9 k mRNA and its regulation by 1,25-dihydroxyvitamin D3 in Caco-2 cells. Arch Biochem Biophys 308:171–174CrossRefPubMedGoogle Scholar
  35. 35.
    Christakos S, Dhawan P, Ajibade D et al (2010) Mechanisms involved in vitamin D mediated intestinal calcium absorption and in non-classical actions of vitamin D. J Steroid Biochem Mol Biol 121:183–187CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Haussler MR, Whitfield GK, Kaneko I et al (2013) Molecular mechanisms of vitamin D action. Calcif Tissue Int 92:77–98CrossRefPubMedGoogle Scholar
  37. 37.
    Suda T, Takahashi N, Martin TJ (1992) Modulation of osteoclast differentiation. Endocr Rev 3:66–80Google Scholar
  38. 38.
    Miao D, He B, Lanske B et al (2004) Skeletal abnormalities in Pth-null mice are influenced by dietary calcium. Endocrinology 145:2046–2053CrossRefPubMedGoogle Scholar
  39. 39.
    Tanaka H, Seino Y (2004) Direct action of 1,25-dihydroxyvitamin D on bone: VDRKO bone shows excessive bone formation in normal mineral condition. J Steroid Biochem Mol Biol 89–90:343–345CrossRefPubMedGoogle Scholar
  40. 40.
    Kim S, Yamazaki M, Zella LA et al (2006) Activation of receptor activator of NF-kappaB ligand gene expression by 1,25-dihydroxyvitamin D3 is mediated through multiple long-range enhancers. Mol Cell Biol 26:6469–6486CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16:139–149CrossRefPubMedGoogle Scholar
  42. 42.
    Mohammadi M, Olsen SK, Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137CrossRefPubMedGoogle Scholar
  43. 43.
    Beenken A, Mohammadi M (2012) The structural biology of the FGF19 subfamily. Adv Exp Med Biol 728:1–24CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    White KE, Evans WE, O’Riordan JLH et al (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26:345–348CrossRefGoogle Scholar
  45. 45.
    Yamashita T (2005) Structural and biochemical properties of fibroblast growth factor 23. Ther Apher Dial 9:313–318CrossRefPubMedGoogle Scholar
  46. 46.
    Kato K, Jeanneau C, Tarp MA et al (2006) Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O‑glycosylation. J Biol Chem 281:18370–18377CrossRefPubMedGoogle Scholar
  47. 47.
    Goetz R, Nakada Y, Hu MC et al (2010) Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci U S A 107:407–412. PubMed: 19966287CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    Bai XY, Miao D, Goltzman D, Karaplis AC (2003) The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J Biol Chem 278(11):9843–9849CrossRefPubMedGoogle Scholar
  49. 49.
    Francis F, Hennig S, Korn B et al (1995) A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 11:130–136CrossRefGoogle Scholar
  50. 50.
    Yamazaki Y, Okazaki R, Shibata M et al (2002) Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 87:4957–4960CrossRefPubMedGoogle Scholar
  51. 51.
    Weber TJ, Liu S, Quarles LD (2003) Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res 18:1227–1234CrossRefPubMedGoogle Scholar
  52. 52.
    Feng JQ, Ward LM, Liu S et al (2006) Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 38:1310–1315CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Turan S, Aydin C, Bereket A, Akcay T, Güran T, Yaralioglu BA, Bastepe M, Jüppner H (2010) Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia. Bone 46:402–409CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Rowe PS (2012) The chicken or the egg: PHEX, FGF23 and SIBLINGs unscrambled. Cell Biochem Funct 30:355–375CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    Huitema LF, Apschner A, Logister I et al (2012) Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish. Proc Natl Acad Sci U S A 109:21372–21377CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    Mackenzie NC, Zhu D, Milne EM et al (2012) Altered bone development and an increase in FGF‑23 expression in Enpp1−/− mice. PLoS One 7(2012)Google Scholar
  57. 57.
    Wohrle S, Bonny O, Beluch N et al (2011) FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. J Bone Miner Res 26:2486–2497CrossRefPubMedGoogle Scholar
  58. 58.
    Wolf M, Koch TA, Bregman DB (2013) Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res 28:1793–1803CrossRefPubMedGoogle Scholar
  59. 59.
    Kuro-o M, Matsumura Y, Aizawa H et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51CrossRefPubMedGoogle Scholar
  60. 60.
    Ichikawa S, Imel EA, Kreiter ML et al (2007) A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117:2684–2691CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Hu MC, Shi M, Zhang J et al (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22:124–136CrossRefPubMedCentralPubMedGoogle Scholar
  62. 62.
    Shimamura Y, Hamada K, Inoue K et al (2012) Serum levels of soluble secreted α-Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis. Clin Exp Nephrol 16:722–729CrossRefPubMedGoogle Scholar
  63. 63.
    Saito H, Maeda A, Ohtomo S et al (2005) Circulating FGF‑23 is regulated by 1α,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 280:2543–2549CrossRefPubMedGoogle Scholar
  64. 64.
    Kolek OI, Hines ER, Jones MD et al (2005) 1{alpha},25-Dihydroxyvitamin D3 upregulates FGF23gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 289(6):G1036–G1042CrossRefPubMedGoogle Scholar
  65. 65.
    Turner AG, Hanrath MA, Morris HA et al (2014) The local production of 1,25(OH)2D3 promotes osteoblast and osteocyte maturation. J Steroid Biochem Mol Biol 144:114–118. doi: 10.1016/j.jsbmb.2013.10.003. pii: S0960-0760(13)00196-9CrossRefPubMedGoogle Scholar
  66. 66.
    Ormsby RT, Findlay DM, Kogawa M et al (2014) Analysis of vitamin D metabolism gene expression in human bone: Evidence for autocrine control of bone remodelling. J Steroid Biochem Mol Biol 144:110–113. doi: 10.1016/j.jsbmb.2013.09.016. pii: S0960-0760(13)00190-8CrossRefPubMedGoogle Scholar
  67. 67.
    Rhee Y, Bivi N, Farrow E et al (2011) Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone 49:636–643CrossRefPubMedCentralPubMedGoogle Scholar
  68. 68.
    Lavi-Moshayoff V, Wasserman G, Meir T et al (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
  69. 69.
    Lopez I, Rodriguez-Ortiz ME, Almaden Y et al (2011) Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo. Kidney Int 80:475–482CrossRefPubMedGoogle Scholar
  70. 70.
    Rodriguez-Ortiz ME, Lopez I, Munoz-Castaneda JR et al (2012) Calcium deficiency reduces circulating levels of FGF23. J Am Soc Nephrol 23:1190–1197CrossRefPubMedCentralPubMedGoogle Scholar
  71. 71.
    Haussler MR, Whitfield GK, Kaneko I et al (2011) The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. Rev Endocr Metab Disord 13:57–69CrossRefGoogle Scholar
  72. 72.
    Sato T, Tominaga Y, Ueki T et al (2004) Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism. Am J Kidney Dis 44:481–487CrossRefPubMedGoogle Scholar
  73. 73.
    Yamashita H, Yamazaki Y, Hasegawa H et al (2007) Fibroblast growth factor-23 (FGF23) in patients with transient hypoparathyroidism: its important role in serum phosphate regulation. Endocr J 54(3):465–470CrossRefPubMedGoogle Scholar
  74. 74.
    Gupta A, Winer K, Econs MJ et al (2004) FGF-23 is elevated by chronic hyperphosphatemia. J Clin Endocrinol Metab 89:4489–4492CrossRefPubMedGoogle Scholar
  75. 75.
    Quinn SJ, Thomsen AR, Pang JL et al (2013) Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo. Am J Physiol Endocrinol Metab 304(3):E310–E320CrossRefPubMedCentralPubMedGoogle Scholar
  76. 76.
    Juppner H, Wolf M (2012) αKlotho: FGF23 coreceptor and FGF23-regulating hormone. J Clin Invest 122:4336–4339CrossRefPubMedCentralPubMedGoogle Scholar
  77. 77.
    Kurosu H, Ogawa Y, Miyoshi M et al (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281:6120–6123CrossRefPubMedCentralPubMedGoogle Scholar
  78. 78.
    Kurosu H, Yamamoto M, Clark JD et al (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833CrossRefPubMedCentralPubMedGoogle Scholar
  79. 79.
    Tohyama O, Imura A, Iwano A et al (2004) Klotho is a novel β-glucuronidase capable of hydrolyzing steroid β-glucuronides. J Biol Chem 279:9777–9784CrossRefPubMedGoogle Scholar
  80. 80.
    Goetz R, Beenken A, Ibrahimi OA et al (2007) Molecular insights into the Klotho dependent, endocrine mode of action of FGF19 subfamily members. Mol Cell Biol 27:3417–3428CrossRefPubMedCentralPubMedGoogle Scholar
  81. 81.
    Urakawa I, Yamazaki Y, Shimada T et al (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770–774CrossRefPubMedGoogle Scholar
  82. 82.
    Murer H, Hernando N, Forster I, Biber J (2003) Regulation of Na/Pi transporter in the proximal tubule. Annu Rev Physiol 65:531–542CrossRefPubMedGoogle Scholar
  83. 83.
    Farrow EG, Davis SI, Summers LJ, White KE (2009) Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol 20:955–960CrossRefPubMedCentralPubMedGoogle Scholar
  84. 84.
    Hu MC, Shi M, Zhang J et al (2010) Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 24:3438–3450CrossRefPubMedCentralPubMedGoogle Scholar
  85. 85.
    Shimada T, Kakitani M, Yamazaki Y et al (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113(4):561–568CrossRefPubMedCentralPubMedGoogle Scholar
  86. 86.
    Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V et al (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117:4003–4008PubMedCentralPubMedGoogle Scholar
  87. 87.
    Krajisnik T, Bjorklund P, Marsell R et al (2007) Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195:125–131CrossRefPubMedGoogle Scholar
  88. 88.
    Canalejo R, Canalejo A, Martinez-Moreno JM et al (2010) FGF23 fails to inhibit uremic parathyroid glands. J Am Soc Nephrol 21:1125–1135CrossRefPubMedCentralPubMedGoogle Scholar
  89. 89.
    Bai X, Miao D, Li J et al (2004) Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. Endocrinology 145(11):5269–5279CrossRefPubMedGoogle Scholar
  90. 90.
    Galitzer H, Ben Dov IZ, Silver J, Naveh-Many T (2010) Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int 77:211–218CrossRefPubMedGoogle Scholar
  91. 91.
    Komaba H, Goto S, Fujii H et al (2010) Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients. Kidney Int 77:232–238CrossRefPubMedGoogle Scholar
  92. 92.
    Hofman-Bang J, Martuseviciene G, Santini MA et al (2010) Increased parathyroid expression of klotho in uremic rats. Kidney Int 78:1119–1127CrossRefPubMedGoogle Scholar
  93. 93.
    Bai X, Miao D, Goltzman D, Karaplis AC (2007) Early lethality in Hyp mice with targeted deletion of Pth gene. Endocrinology 148(10):497CrossRefGoogle Scholar
  94. 94.
    Slatopolsky E, Finch J, Denda M et al (1996) Phosphorus restriction prevents parathyroid gland growth-high phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 97:2534–2540CrossRefPubMedCentralPubMedGoogle Scholar

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© Springer-Verlag Italia 2015

Authors and Affiliations

  1. 1.Calcium Research Laboratory and Department of MedicineMcGill University Health Centre, Royal Victoria HospitalMontrealCanada
  2. 2.Departments of Medicine and PhysiologyMcGill UniversityMontrealCanada
  3. 3.Division of Endocrinology, Department of Medicine and Lady Davis Institute for Medical ResearchJewish General Hospital, McGill UniversityMontrealCanada

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