Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation

Article

Abstract

Phosphorous is essential for multiple cellular functions and constitutes an important mineral in bone. Hypophosphatemia in children leads to rickets resulting in abnormal growth and often skeletal deformities. Among various causes of low serum phosphorous are inherited disorders associated with increased urinary excretion of phosphate, including autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemia (ARHP), and hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Recent genetic analyses and subsequent biochemical and animal studies have revealed several novel molecules that appear to play key roles in the regulation of renal phosphate handling. These include a protein with abundant expression in bone, fibroblast growth factor 23 (FGF23), which has proven to be a circulating hormone that inhibits tubular reabsorption of phosphate in the kidney. Two other bone-specific proteins, PHEX and dentin matrix protein 1 (DMP1), appear to be necessary for limiting the expression of fibroblast growth factor 23, thereby allowing sufficient renal conservation of phosphate. This review focuses on the clinical, biochemical, and genetic features of inherited hypophosphatemic disorders, and presents the current understanding of hormonal and molecular mechanisms that govern phosphorous homeostasis.

Keywords

Hypophosphatemic disorders Phosphorus Vitamin D PTH FGF23 PHEX DMP1 

References

  1. 1.
    Miller WL, Portale AA. Genetic causes of rickets. Curr Opin Pediatr. 1999;11:333–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Demay MB, Sabbagh Y, Carpenter TO. Calcium and vitamin D: what is known about the effects on growing bone. Pediatrics. 2007;119 Suppl 2:S141–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Jüppner H, Thakker R. Genetic disorders of calcium and phosphate homeostasis. In: Pollak M (ed) The kidney. W.B. Saunders Company, Philadelphia, PA; 2008. (in press).Google Scholar
  4. 4.
    Sabbagh Y, Carpenter TO, Demay MB. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl Acad Sci U S A. 2005;102:9637–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Forster IC, Hernando N, Biber J, Murer H. Proximal tubular handling of phosphate: a molecular perspective. Kidney Int. 2006;70:1548–59.PubMedCrossRefGoogle Scholar
  6. 6.
    Tenenhouse HS. Phosphate transport: molecular basis, regulation and pathophysiology. J Steroid Biochem Mol Biol. 2007;103:572–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Miyamoto K, Ito M, Tatsumi S, Kuwahata M, Segawa H. New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphate transporter. Am J Nephrol. 2007;27:503–15.PubMedCrossRefGoogle Scholar
  8. 8.
    St-Arnaud R, Demay MB. Vitamin D biology. In: Glorieux FH, Juppner H, Pettifor JM, editors. Pediatric bone: biology and diseases. San Diego: Academic; 2003. p. 193–216.Google Scholar
  9. 9.
    Jüppner H, Gardella T, Brown E, Kronenberg H, Potts J Jr. Parathyroid hormone and parathyroid hormone-related peptide in the regulation of calcium homeostasis and bone development. In: DeGroot L, Jameson J, editors. Endocrinology. 5th ed. Philadelphia, PA: W.B. Saunders Company; 2005. p. 1377–417.Google Scholar
  10. 10.
    Mensenkamp AR, Hoenderop JG, Bindels RJ. TRPV5, the gateway to Ca2+ homeostasis. Handb Exp Pharmacol. 2007;179:207–20.PubMedGoogle Scholar
  11. 11.
    Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–81.PubMedCrossRefGoogle Scholar
  12. 12.
    Portale AA, Miller WL. Rickets due to hereditary abnormalities of vitamin D synthesis and action. In: Glorieux FH, Juppner H, Pettifor JM, editors. Pediatric bone: biology and diseases. San Diego: Academic; 2003. p. 583–602.Google Scholar
  13. 13.
    Holm IA, Econs MJ, Carpenter TO. Familial hypophosphatemia and related disorders. In: Glorieux FH, Juppner H, Pettifor JM, editors. Pediatric bone: biology and diseases. San Diego, CA: Academic; 2003. p. 603–31.Google Scholar
  14. 14.
    White K, Larsson T, Econs M. The roles of specific genes implicated as circulating factors involved in normal and disordered phosphate homeostasis: Frp-4, MEPE, and FGF23. Endocr Rev. 2006;27 3:221–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Econs M, Drezner M. Tumor-induced osteomalacia—unveiling a new hormone. N Engl J Med. 1994;330:1679–81.PubMedCrossRefGoogle Scholar
  16. 16.
    ADHR Consortium T; White KE, Evans WE, O’Riordan JLH, Speer MC, Econs MJ, et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26:345–8.CrossRefGoogle Scholar
  17. 17.
    Bianchine JW, Stambler AA, Harrison HE. Familial hypophosphatemic rickets showing autosomal dominant inheritance. Birth Defects Orig Artic Ser. 1971;7:287–95.PubMedGoogle Scholar
  18. 18.
    Econs M, McEnery P. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab. 1997;82:674–81.PubMedCrossRefGoogle Scholar
  19. 19.
    Econs M, McEnery P, Lennon F, Speer M. Autosomal dominant hypophosphatemic rickets is linked to chromosome 12p13. J Clin Invest. 1997;100:2653–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J. Bone Mineral Res. 2007;22(4):520–6 (Apr).CrossRefGoogle Scholar
  21. 21.
    Kruse K, Woelfel D, Strom T. Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation. Horm Res. 2001;55:305–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest. 2004;113:561–8.PubMedGoogle Scholar
  23. 23.
    Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, et al. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol. 2004;23:421–32.PubMedCrossRefGoogle Scholar
  24. 24.
    Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD. Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab. 2006;291:E38–49.PubMedCrossRefGoogle Scholar
  25. 25.
    Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA. 2001;98:6500–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology. 2002;143:3179–82.PubMedCrossRefGoogle Scholar
  27. 27.
    Benet-Pages A, Lorenz-Depiereux B, Zischka H, White K, Econs M, Strom T. FGF23 is processed by proprotein convertases but not by PHEX. Bone. 2004;35:455–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Berndt TJ, Craig TA, McCormick DJ, Lanske B, Sitara D, Razzaque MS, et al. Biological activity of FGF-23 fragments. Pflugers Arch. 2007;454:615–23.PubMedCrossRefGoogle Scholar
  29. 29.
    Jan De Beur S, Finnegan R, Vassiliadis J, Cook B, Barberio D, Estes S, et al. Tumors associated with oncogenic osteomalacia express genes important in bone and mineral metabolism. J Bone Miner Res. 2002;17:1102–10.CrossRefGoogle Scholar
  30. 30.
    White K, Jonsson K, Carn G, Hampson G, Spector T, Mannstadt M, et al. The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J Clin Endocrinol Metab. 2001;86:497–500.PubMedCrossRefGoogle Scholar
  31. 31.
    Topaz O, Shurman D, Bergman R, Indelman M, Ratajczak P, Mizrachi M, et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet. 2004;36:579–81.PubMedCrossRefGoogle Scholar
  32. 32.
    Ichikawa S, Lyles K, Econs M. A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive. J Clin Endocrinol Metab. 2005;90:2420–3.PubMedCrossRefGoogle Scholar
  33. 33.
    Perwad F, Azam N, Zhang M, Yamashita T, Tenenhouse H, Portale A. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology. 2005;146:5358–64.PubMedCrossRefGoogle Scholar
  34. 34.
    Perwad F, Zhang MY, Tenenhouse HS, Portale AA. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. Am J Physiol Renal Physiol. 2007;293:F1577–83.PubMedCrossRefGoogle Scholar
  35. 35.
    Ferrari S, Bonjour J, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab. 2005;90:1519–24.PubMedCrossRefGoogle Scholar
  36. 36.
    Burnett S, Gunawardene S, Bringhurst F, Jüppner H, Lee H, Finkelstein J. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res. 2006;21:1187–96.PubMedCrossRefGoogle Scholar
  37. 37.
    Consortium TH. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat Genet. 1995;11:130–6.CrossRefGoogle Scholar
  38. 38.
    Holm IA, Huang X, Kunkel LM. Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets. Am J Hum Genet. 1997;60:790–7.PubMedGoogle Scholar
  39. 39.
    Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab. 2002;87:4957–60.PubMedCrossRefGoogle Scholar
  40. 40.
    Jonsson K, Zahradnik R, Larsson T, White K, Sugimoto T, Imanishi Y, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. New Engl J Med. 2003;348:1656–62.PubMedCrossRefGoogle Scholar
  41. 41.
    Weber T, Liu S, Indridason O, Quarles L. Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res. 2003;18:1227–34.PubMedCrossRefGoogle Scholar
  42. 42.
    Aono Y, Shimada T, Yamazaki Y, Hino R, Takeuchi M, Fujita T, et al. The neutralization of FGF-23 ameliorates hypophosphatemia and rickets in Hyp mice. Meeting of the American Society for Bone and Mineral Research, Minneapolis, Minnesota, 2003; p 1056.Google Scholar
  43. 43.
    Liu S, Brown T, Zhou J, Xiao Z, Awad H, Guilak F, et al. Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia. J Am Soc Nephrol. 2005;16:91645–53.PubMedCrossRefGoogle Scholar
  44. 44.
    Bowe A, Finnegan R, Jan de Beur S, Cho J, Levine M, Kumar R, et al. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun. 2001;284:977–81.PubMedCrossRefGoogle Scholar
  45. 45.
    Perry W, Stamp T. Hereditary hypophosphataemic rickets with autosomal recessive inheritance and severe osteosclerosis. A report of two cases. J Bone Joint Surg Br. 1978;60-B:430–4.PubMedGoogle Scholar
  46. 46.
    Scriver C, Reade T, Halal F, Costa T, Cole D. Autosomal hypophosphataemic bone disease responds to 1,25-(OH)2D3. Arch Dis Child. 1981;56:203–7.PubMedGoogle Scholar
  47. 47.
    Bastepe M, Shlossberg H, Murdock H, Jüppner H, Rittmaster R. A Lebanese family with osteosclerosis and hypophosphatemia. J Bone Miner Res. 1999;14:S558.Google Scholar
  48. 48.
    Lorenz-Depiereux B, Bastepe M, Benet-Pagès A, Amyere M, Wagenstaller J, Müller-Barth U, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet. 2006;38:1248–50.PubMedCrossRefGoogle Scholar
  49. 49.
    Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006;38:1310–5.PubMedCrossRefGoogle Scholar
  50. 50.
    George A, Sabsay B, Simonian PA, Veis A. Characterization of a novel dentin matrix acidic phosphoprotein. Implications for induction of biomineralization. J Biol Chem. 1993;268:12624–30.PubMedGoogle Scholar
  51. 51.
    Narayanan K, Ramachandran A, Hao J, He G, Park KW, Cho M, et al. Dual functional roles of dentin matrix protein 1. Implications in biomineralization and gene transcription by activation of intracellular Ca2+ store. J Biol Chem. 2003;278:17500–8.PubMedCrossRefGoogle Scholar
  52. 52.
    George A, Ramachandran A, Albazzaz M, Ravindran S. DMP1—a key regulator in mineralized matrix formation. J Musculoskelet Neuronal Interact. 2007;7:308.PubMedGoogle Scholar
  53. 53.
    Lu Y, Liu S, Yu S, Xie Y, Zhou J, Quarles L, et al. The 57 kDa C-terminal fragment of Dentin Matrix Protein 1 (DMP1) retains all biological activity: Osteocytic regulation of Pi homeostasis through FGF23. 29. Annual Meeting of American Society Bone and Mineral Research, Honolulu, Hawai, 2007.Google Scholar
  54. 54.
    Ye L, Mishina Y, Chen D, Huang H, Dallas S, Dallas M, et al. Dmp1-deficient mice display severe defects in cartilage formation responsible for a chondrodysplasia-like phenotype. J Biol Chem. 2005;280:6197–203.PubMedCrossRefGoogle Scholar
  55. 55.
    Feng JQ, Scott G, Guo D, Jiang B, Harris M, Ward T, et al. Generation of a conditional null allele for Dmp1 in mouse. Genesis. 2008;46:87–91.PubMedCrossRefGoogle Scholar
  56. 56.
    Lu Y, Xie Y, Zhang S, Dusevich V, Bonewald LF, Feng JQ. DMP1-targeted Cre expression in odontoblasts and osteocytes. J Dent Res. 2007;86:320–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Beighton P. Osteoglophonic dysplasia. J Med Genet. 1989;26:572–6.PubMedGoogle Scholar
  58. 58.
    Beighton P, Cremin BJ, Kozlowski K. Osteoglophonic dwarfism. Pediatr Radiol. 1980;10:46–50.PubMedCrossRefGoogle Scholar
  59. 59.
    White K, Cabral J, Evans W, Ichikawa S, Davis S, Ornitz D, et al. A missense mutation in FGFR1 causes a novel syndrome: craniofacial dysplasia with hypophosphatemia (CFDH). J Bone Miner Res. 2003;18 Suppl 2:S4.Google Scholar
  60. 60.
    Farrow E, Davis S, Mooney S, Beighton P, Mascarenhas L, Gutierrez Y, et al. Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. Am J Med Genet. 2006;140:537–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Muenke M, Schell U, Hehr A, Robin NH, Losken HW, Schinzel A, et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet. 1994;8:269–74.PubMedCrossRefGoogle Scholar
  62. 62.
    Roscioli T, Flanagan S, Kumar P, Masel J, Gattas M, Hyland VJ, et al. Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature. Am J Med Genet. 2000;93:22–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Hoffman W, Jüppner H, Deyoung B, O’dorisio M, Given K. Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A. 2005;134:233–6.PubMedGoogle Scholar
  64. 64.
    Heike C, Cunningham M, Steiner R, Wenkert D, Hornung R, Gruss J, et al. Skeletal changes in epidermal nevus syndrome: does focal bone disease harbor clues concerning pathogenesis? Am J Med Genet A. 2005;139:67–77.PubMedGoogle Scholar
  65. 65.
    Weinstein L, Yu S, Warner D, Liu J. Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev. 2001;22:675–705.PubMedCrossRefGoogle Scholar
  66. 66.
    Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. New Engl J Med. 1991;325:1688–95.PubMedCrossRefGoogle Scholar
  67. 67.
    Schwindinger W, Francomano C, Levine M. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune–Albright syndrome. Proc Natl Acad Sci U S A. 1992;89:5152–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Riminucci M, Collins M, Fedarko N, Cherman N, Corsi A, White K, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. 2003;112:683–92.PubMedGoogle Scholar
  69. 69.
    Kobayashi K, Imanishi Y, Koshiyama H, Miyauchi A, Wakasa K, Kawata T, et al. Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia. Life Sci. 2006;78:2295–301.PubMedCrossRefGoogle Scholar
  70. 70.
    Yamamoto T, Imanishi Y, Kinoshita E, Nakagomi Y, Shimizu N, Miyauchi A, et al. The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune–Albright syndrome. J Bone Miner Metab. 2005;23:231–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Ntp2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci U S A. 1998;95:5372–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Tieder M, Modai D, Samuel R, Arie R, Halabe A, Bab I, et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med. 1985;312:611–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Tieder M, Modai D, Shaked U, Samuel R, Arie R, Halabe A, et al. “Idiopathic” hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect. N Engl J Med. 1987;316:125–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium/phosphate cotransporter gene SLC34A3. Am J Human Genet. 2006;78 2:193–201.CrossRefGoogle Scholar
  75. 75.
    Yamamoto T, Michigami T, Aranami F, Segawa H, Yoh K, Nakajima S, et al. Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene type IIc and osteoblastic function. J Bone Miner Metab. 2007;25:407–13.PubMedCrossRefGoogle Scholar
  76. 76.
    Jones A, Tzenova J, Frappier D, Crumley M, Roslin N, Kos C, et al. Hereditary hypophosphatemic rickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene. J Am Soc Nephrol. 2001;12:507–14.PubMedGoogle Scholar
  77. 77.
    Bergwitz C, Roslin N, Tieder M, Loredo-Osti J, Bastepe M, Abu-Zahra H, et al. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) predict a key role for the sodium-phosphate co-transporter NaPi-IIc in maintaining phosphate homeostasis and skeletal function. Am J Human Genet. 2006;78 2:179–92.CrossRefGoogle Scholar
  78. 78.
    Ichikawa S, Sorenson AH, Imel EA, Friedman NE, Gertner JM, Econs MJ. Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab. 2006;91:4022–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Prié D, Huart V, Bakouh N, Planelles G, Dellis O, Gérard B, et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med. 2002;347:983–91.PubMedCrossRefGoogle Scholar
  80. 80.
    Virkki L, Forster I, Hernando N, Biber J, Murer H. Functional characterization of two naturally occurring mutations in the human sodium-phosphate cotransporter type IIa. J Bone Miner Res. 2003;18:2135–41.PubMedCrossRefGoogle Scholar
  81. 81.
    Lapointe JY, Tessier J, Paquette Y, Wallendorff B, Coady MJ, Pichette V, et al. NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kidney Int. 2006;69:2261–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Walton RJ, Bijvoet OL. Nomogram for derivation of renal threshold phosphate concentration. Lancet. 1975;2:309–10.PubMedCrossRefGoogle Scholar
  83. 83.
    Yamashita T, Konishi M, Miyake A, Inui K, Itoh N. Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of the mitogen-activated protein kinase pathway. J Biol Chem. 2002;277:28265–70.PubMedCrossRefGoogle Scholar
  84. 84.
    Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, et al. Regulation of fibroblast growth factor-23 signaling by Klotho. J Biol Chem. 2006;281:6120–3.PubMedCrossRefGoogle Scholar
  86. 86.
    Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest. 2007;117:2684–91.PubMedCrossRefGoogle Scholar
  87. 87.
    Kato Y, Arakawa E, Kinoshita S, Shirai A, Furuya A, Yamano K, et al. Establishment of the anti-Klotho monoclonal antibodies and detection of Klotho protein in kidneys. Biochem Biophys Res Commun. 2000;267:597–602.PubMedCrossRefGoogle Scholar
  88. 88.
    Li SA, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct. 2004;29:91–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, et al. 1alpha,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal–gastrointestinal–skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol. 2005;289:G1036–42.PubMedCrossRefGoogle Scholar
  90. 90.
    Masuyama R, Stockmans I, Torrekens S, Van Looveren R, Maes C, Carmeliet P, et al. Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts. J Clin Invest. 2006;116:3150–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro OM, Mohammadi M, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest. 2007;117:4003–8.PubMedGoogle Scholar
  92. 92.
    Krajisnik T, Bjorklund P, Marsell R, Ljunggren O, Akerstrom G, Jonsson KB, et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol. 2007;195:125–31.PubMedCrossRefGoogle Scholar
  93. 93.
    Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.PubMedCrossRefGoogle Scholar
  94. 94.
    Nabeshima Y. Klotho: a fundamental regulator of aging. Ageing Res Rev. 2002;1:627–38.PubMedCrossRefGoogle Scholar
  95. 95.
    Kawata T, Imanishi Y, Kobayashi K, Miki T, Arnold A, Inaba M, et al. Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism. J Am Soc Nephrol. 2007;18:2683–8.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Endocrine UnitMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Pediatric Nephrology UnitMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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