Osteocyte Communication with the Kidney Via the Production of FGF23: Remote Control of Phosphate Homeostasis

  • Nobuaki Ito
  • David M. Findlay
  • Gerald J. AtkinsEmail author
Original Paper


Osteocytes have emerged as the principal controlling cell type in bone. It is now clear that osteocytes communicate with each other, with other key bone cell types and also function as a vital endocrine organ. In this review, we will focus on one such humoral factor produced by osteocytes, fibroblast growth factor 23 and the involvement of this key phosphate-regulating hormone in human disease.


FGF23 Osteocyte Hormone Phosphate Hypophosphataemia Rickets Osteomalacia 



Conflict of interest

Nobuaki Ito, David M. Findlay and Gerald J. Atkins declare that they have no conflict of interest.

Animal/Human studies

This article does not contain any studies with human or animal subjects performed by any of the authors.


  1. 1.
    Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229–38. doi: 10.1002/jbmr.320.PubMedGoogle Scholar
  2. 2.
    Atkins G, Findlay D. Osteocyte regulation of bone mineral: a little give and take. Osteoporos Int. 2012;8:2067–79. doi: 10.1007/s00198-012-1915-z.Google Scholar
  3. 3.
    Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130(3):456–69.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Fukumoto S, Yamashita T. FGF23 is a hormone-regulating phosphate metabolism—unique biological characteristics of FGF23. Bone. 2007;40(5):1190–5. doi: 10.1016/j.bone.2006.12.062.PubMedGoogle Scholar
  5. 5.
    Rowe PS. The chicken or the egg: PHEX, FGF23 and SIBLINGs unscrambled. Cell Biochem Funct. 2012;30(5):355–75. doi: 10.1002/cbf.2841.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Feng JQ, Clinkenbeard EL, Yuan B, White KE, Drezner MK. Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone. 2013;54(2):213–21. doi: 10.1016/j.bone.2013.01.046.PubMedGoogle Scholar
  7. 7.
    Quarles LD. A systems biology preview of the relationships between mineral and metabolic complications in chronic kidney disease. Semin Nephrol. 2013;33(2):130–42. doi: 10.1016/j.semnephrol.2012.12.014.PubMedGoogle Scholar
  8. 8.
    Consortium TA. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26(3):345–8. doi: 10.1038/81664.Google Scholar
  9. 9.
    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(11):6500–5.PubMedGoogle Scholar
  10. 10.
    Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19(3):429–35. doi: 10.1359/JBMR.0301264.PubMedGoogle Scholar
  11. 11.
    Segawa H, Kawakami E, Kaneko I, Kuwahata M, Ito M, Kusano K, et al. Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter. Pflug Arch. 2003;446(5):585–92. doi: 10.1007/s00424-003-1084-1.Google Scholar
  12. 12.
    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 Investig. 2004;113(4):561–8.PubMedGoogle Scholar
  13. 13.
    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(7):421–32. doi: 10.1016/j.matbio.2004.09.007.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun. 2004;314(2):409–14. doi: 10.1016/j.bbrc.2003.12.102.PubMedGoogle Scholar
  15. 15.
    Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun. 2000;277(2):494–8. doi: 10.1006/bbrc2000.3696.PubMedGoogle Scholar
  16. 16.
    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(7120):770–4. doi: 10.1038/nature05315.PubMedGoogle Scholar
  17. 17.
    Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, et al. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem. 2007;282(37):26687–95. doi: 10.1074/jbc.M704165200.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, et al. Alpha-Klotho as a regulator of calcium homeostasis. Science. 2007;316(5831):1615–8. doi: 10.1126/science.1135901.PubMedGoogle Scholar
  19. 19.
    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(6655):45–51. doi: 10.1038/36285.PubMedGoogle Scholar
  20. 20.
    Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Investig. 2003;112(5):683–92. doi: 10.1172/JCI200318399.PubMedGoogle Scholar
  21. 21.
    Ubaidus S, Li M, Sultana S, de Freitas PH, Oda K, Maeda T, et al. FGF23 is mainly synthesized by osteocytes in the regularly distributed osteocytic lacunar canalicular system established after physiological bone remodeling. J Electron Microsc (Tokyo). 2009;58(6):381–92. doi: 10.1093/jmicro/dfp032.Google Scholar
  22. 22.
    Woo SM, Rosser J, Dusevich V, Kalajzic I, Bonewald LF. Cell line IDG-SW3 replicates osteoblast-to-late-osteocyte differentiation in vitro and accelerates bone formation in vivo. J Bone Miner Res. 2011;26(11):2634–46. doi: 10.1002/jbmr.465.PubMedCentralPubMedGoogle Scholar
  23. 23.
    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(8):3179–82.PubMedGoogle Scholar
  24. 24.
    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(11):4957–60.PubMedGoogle Scholar
  25. 25.
    Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003;348(17):1656–63. doi: 10.1056/NEJMoa020881.PubMedGoogle Scholar
  26. 26.
    Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. 2007;22(4):520–6. doi: 10.1359/jbmr.070107.PubMedGoogle Scholar
  27. 27.
    Farrow EG, Yu X, Summers LJ, Davis SI, Fleet JC, Allen MR, et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci USA. 2011;108(46):E1146–55. doi: 10.1073/pnas.1110905108.PubMedGoogle Scholar
  28. 28.
    Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011;96(11):3541–9. doi: 10.1210/jc.2011-1239.PubMedGoogle Scholar
  29. 29.
    Burnett CH, Dent CE, Harper C, Warland BJ. Vitamin D-resistant rickets. Analysis of twenty-four pedigrees with hereditary and sporadic cases. Am J Med. 1964;36:222–32.PubMedGoogle Scholar
  30. 30.
    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(2):130–6. doi: 10.1038/ng1095-130.Google Scholar
  31. 31.
    Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology. 2005;146(12):5358–64. doi: 10.1210/en.2005-0777.PubMedGoogle Scholar
  32. 32.
    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(11):1310–5.PubMedCentralPubMedGoogle Scholar
  33. 33.
    Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-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(11):1248–50.PubMedGoogle Scholar
  34. 34.
    Feng JQ, Huang H, Lu Y, Ye L, Xie Y, Tsutsui TW, et al. The dentin matrix protein 1 (Dmp1) is specifically expressed in mineralized, but not soft, tissues during development. J Dent Res. 2003;82(10):776–80.PubMedGoogle Scholar
  35. 35.
    Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010;86(2):267–72. doi: 10.1016/j.ajhg.2010.01.006.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010;86(2):273–8. doi: 10.1016/j.ajhg.2010.01.010.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, et al. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet. 2003;34(4):379–81. doi: 10.1038/ng1221.PubMedGoogle Scholar
  38. 38.
    Saito T, Shimizu Y, Hori M, Taguchi M, Igarashi T, Fukumoto S, et al. A patient with hypophosphatemic rickets and ossification of posterior longitudinal ligament caused by a novel homozygous mutation in ENPP1 gene. Bone. 2011;49(4):913–6. doi: 10.1016/j.bone.2011.06.029.PubMedGoogle Scholar
  39. 39.
    Mehta P, Mitchell A, Tysoe C, Caswell R, Owens M, Vincent T. Novel compound heterozygous mutations in ENPP1 cause hypophosphataemic rickets with anterior spinal ligament ossification. Rheumatology (Oxford). 2012;. doi: 10.1093/rheumatology/kes089.Google Scholar
  40. 40.
    Nurnberg P, Thiele H, Chandler D, Hohne W, Cunningham ML, Ritter H, et al. Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat Genet. 2001;28(1):37–41. doi: 10.1038/88236.PubMedGoogle Scholar
  41. 41.
    Pendleton A, Johnson MD, Hughes A, Gurley KA, Ho AM, Doherty M, et al. Mutations in ANKH cause chondrocalcinosis. Am J Hum Genet. 2002;71(4):933–40. doi: 10.1086/343054.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Morava E, Kuhnisch J, Drijvers JM, Robben JH, Cremers C, van Setten P, et al. Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family. J Clin Endocrinol Metab. 2011;96(1):E189–98. doi: 10.1210/jc.2010-1539.PubMedGoogle Scholar
  43. 43.
    Chen IP, Wang L, Jiang X, Aguila HL, Reichenberger EJ. A Phe377del mutation in ANK leads to impaired osteoblastogenesis and osteoclastogenesis in a mouse model for craniometaphyseal dysplasia (CMD). Hum Mol Genet. 2011;20(5):948–61. doi: 10.1093/hmg/ddq541.PubMedGoogle Scholar
  44. 44.
    Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, et al. Exome sequencing reveals FAM20c mutations associated with FGF23-related hypophosphatemia, dental anomalies and ectopic calcification. J Bone Miner Res. 2013;. doi: 10.1002/jbmr.1850.PubMedGoogle Scholar
  45. 45.
    Wang X, Wang S, Li C, Gao T, Liu Y, Rangiani A, et al. Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS Genet. 2012;8(5):e1002708. doi: 10.1371/journal.pgen.1002708.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Simpson MA, Hsu R, Keir LS, Hao J, Sivapalan G, Ernst LM, et al. Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am J Hum Genet. 2007;81(5):906–12. doi: 10.1086/522240.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Brown WW, Juppner H, Langman CB, Price H, Farrow EG, White KE, et al. Hypophosphatemia with elevations in serum fibroblast growth factor 23 in a child with Jansen’s metaphyseal chondrodysplasia. J Clin Endocrinol Metab. 2009;94(1):17–20. doi: 10.1210/jc.2008-0220.PubMedGoogle Scholar
  48. 48.
    Rhee Y, Bivi N, Farrow E, Lezcano V, Plotkin LI, White KE, et al. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone. 2011;49(4):639–43. doi: 10.1016/j.bone.2011.06.025.Google Scholar
  49. 49.
    Yamashita H, Yamashita T, Miyamoto M, Shigematsu T, Kazama JJ, Shimada T, et al. Fibroblast growth factor (FGF)-23 in patients with primary hyperparathyroidism. Eur J Endocrinol. 2004;151(1):55–60.PubMedGoogle Scholar
  50. 50.
    Burnett-Bowie SM, Henao MP, Dere ME, Lee H, Leder BZ. Effects of hPTH(1-34) infusion on circulating serum phosphate, 1,25-dihydroxyvitamin D, and FGF23 levels in healthy men. J Bone Miner Res. 2009;24(10):1681–5. doi: 10.1359/jbmr.090406.PubMedGoogle Scholar
  51. 51.
    Lupp A, Klenk C, Rocken C, Evert M, Mawrin C, Schulz S. Immunohistochemical identification of the PTHR1 parathyroid hormone receptor in normal and neoplastic human tissues. Eur J Endocrinol. 2010;162(5):979–86. doi: 10.1530/EJE-09-0821.PubMedGoogle Scholar
  52. 52.
    White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, et al. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet. 2005;76(2):361–7. doi: 10.1086/427956.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Martin A, Liu S, David V, Li H, Karydis A, Feng JQ, et al. Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J. 2011;25(8):2551–62. doi: 10.1096/fj.10-177816.PubMedGoogle Scholar
  54. 54.
    Wohrle S, Bonny O, Beluch N, Gaulis S, Stamm C, Scheibler M, et al. 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. 2011;26(10):2486–97. doi: 10.1002/jbmr.478.PubMedGoogle Scholar
  55. 55.
    Wu AL, Feng B, Chen MZ, Kolumam G, Zavala-Solorio J, Wyatt SK, et al. Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. PLoS One. 2013;8(2):e57322. doi: 10.1371/journal.pone.0057322.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, et al. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci USA. 2008;105(9):3455–60. doi: 10.1073/pnas.0712361105.PubMedGoogle Scholar
  57. 57.
    Smith RC, O’Bryan LM, Farrow EG, Summers LJ, Clinkenbeard EL, Roberts JL, et al. Circulating alphaKlotho influences phosphate handling by controlling FGF23 production. J Clin Investig. 2012;122(12):4710–5. doi: 10.1172/JCI64986.PubMedGoogle Scholar
  58. 58.
    Ito N, Atkins GJ, Findlay DM. eLetters for [Circulating alphaKlotho influences phosphate handling by controlling FGF23 production]. J Clin Investig. 2012. [Epub only].
  59. 59.
    Dent CE, Gertner JM. Hypophosphataemic osteomalacia in fibrous dysplasia. Q J Med. 1976;45(179):411–20.PubMedGoogle Scholar
  60. 60.
    Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N Engl J Med. 1991;325(24):1688–95. doi: 10.1056/NEJM199112123252403.PubMedGoogle Scholar
  61. 61.
    Jiang Y, Xia WB, Xing XP, Silva BC, Li M, Wang O, et al. Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: report of 39 cases and review of the literature. J Bone Miner Res. 2012;27(9):1967–75. doi: 10.1002/jbmr.1642.PubMedGoogle Scholar
  62. 62.
    Schouten BJ, Doogue MP, Soule SG, Hunt PJ. Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia. Ann Clin Biochem. 2009;46(Pt 2):167–9. doi: 10.1258/acb.2008.008151.PubMedGoogle Scholar
  63. 63.
    Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab. 2009;94(7):2332–7. doi: 10.1210/jc.2008-2396.PubMedGoogle Scholar
  64. 64.
    Shimizu Y, Tada Y, Yamauchi M, Okamoto T, Suzuki H, Ito N, et al. Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: another form of FGF23-related hypophosphatemia. Bone. 2009;45(4):814–6. doi: 10.1016/j.bone.2009.06.017.PubMedGoogle Scholar
  65. 65.
    Prentice A, Ceesay M, Nigdikar S, Allen SJ, Pettifor JM. FGF23 is elevated in Gambian children with rickets. Bone. 2008;42(4):788–97. doi: 10.1016/j.bone.2007.11.014.PubMedGoogle Scholar
  66. 66.
    Braithwaite V, Bruggraber SF, Prentice A. Intact fibroblast growth factor 23 and fragments in plasma from Gambian children. Osteoporos Int. 2013;24(3):1121–4. doi: 10.1007/s00198-012-2029-3.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Braithwaite V, Jarjou LM, Goldberg GR, Prentice A. Iron status and fibroblast growth factor-23 in Gambian children. Bone. 2012;50(6):1351–6. doi: 10.1016/j.bone.2012.03.010.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013;. doi: 10.1002/jbmr.1923.PubMedGoogle Scholar
  69. 69.
    Ito N, Fukumoto S, Takeuchi Y, Yasuda T, Hasegawa Y, Takemoto F, et al. Comparison of two assays for fibroblast growth factor (FGF)-23. J Bone Miner Metab. 2005;23(6):435–40. doi: 10.1007/s00774-005-0625-4.PubMedGoogle Scholar
  70. 70.
    Imel EA, Peacock M, Pitukcheewanont P, Heller HJ, Ward LM, Shulman D, et al. Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia. J Clin Endocrinol Metab. 2006;91(6):2055–61. doi: 10.1210/jc.2005-2105.PubMedGoogle Scholar
  71. 71.
    Endo I, Fukumoto S, Ozono K, Namba N, Tanaka H, Inoue D, et al. Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: proposal of diagnostic criteria using FGF23 measurement. Bone. 2008;42(6):1235–9. doi: 10.1016/j.bone.2008.02.014.Google Scholar
  72. 72.
    Aono Y, Hasegawa H, Yamazaki Y, Shimada T, Fujita T, Yamashita T, et al. Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. J Bone Miner Res. 2011;26(4):803–10. doi: 10.1002/jbmr.275.PubMedGoogle Scholar
  73. 73.
    Wohrle S, Henninger C, Bonny O, Thuery A, Beluch N, Hynes NE, et al. Pharmacological inhibition of FGFR signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res. 2012;. doi: 10.1002/jbmr.1810.Google Scholar
  74. 74.
    Lyles KW, Halsey DL, Friedman NE, Lobaugh B. Correlations of serum concentrations of 1,25-dihydroxyvitamin D, phosphorus, and parathyroid hormone in tumoral calcinosis. J Clin Endocrinol Metab. 1988;67(1):88–92.PubMedGoogle Scholar
  75. 75.
    Beck DA, Gray L, Lyles KW. Dementia associated with hyperphosphatemic tumoral calcinosis. Clin Neurol Neurosurg. 1998;100(2):121–5.PubMedGoogle Scholar
  76. 76.
    Adams WM, Laitt RD, Davies M, O’Donovan DG. Familial tumoral calcinosis: association with cerebral and peripheral aneurysm formation. Neuroradiology. 1999;41(5):351–5.PubMedGoogle Scholar
  77. 77.
    Ichikawa S, Imel EA, Sorenson AH, Severe R, Knudson P, Harris GJ, et al. Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene. J Clin Endocrinol Metab. 2006;91(11):4472–5. doi: 10.1210/jc.2006-1247.PubMedGoogle Scholar
  78. 78.
    Campagnoli MF, Pucci A, Garelli E, Carando A, Defilippi C, Lala R, et al. Familial tumoral calcinosis and testicular microlithiasis associated with a new mutation of GALNT3 in a white family. J Clin Pathol. 2006;59(4):440–2. doi: 10.1136/jcp.2005.026369.PubMedGoogle Scholar
  79. 79.
    Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet. 2005;14(3):385–90. doi: 10.1093/hmg/ddi034.PubMedGoogle Scholar
  80. 80.
    Larsson T, Davis SI, Garringer HJ, Mooney SD, Draman MS, Cullen MJ, et al. Fibroblast growth factor-23 mutants causing familial tumoral calcinosis are differentially processed. Endocrinology. 2005;146(9):3883–91. doi: 10.1210/en.2005-0431.PubMedGoogle Scholar
  81. 81.
    Araya K, Fukumoto S, Backenroth R, Takeuchi Y, Nakayama K, Ito N, et al. A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab. 2005;90(10):5523–7. doi: 10.1210/jc.2005-0301.PubMedGoogle Scholar
  82. 82.
    Chefetz I, Heller R, Galli-Tsinopoulou A, Richard G, Wollnik B, Indelman M, et al. A novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification. Hum Genet. 2005;118(2):261–6. doi: 10.1007/s00439-005-0026-8.PubMedGoogle Scholar
  83. 83.
    Garringer HJ, Malekpour M, Esteghamat F, Mortazavi SM, Davis SI, Farrow EG, et al. Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis. Am J Physiol Endocrinol Metab. 2008;295(4):E929–37. doi: 10.1152/ajpendo.90456.2008.PubMedGoogle Scholar
  84. 84.
    Topaz O, Shurman DL, 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(6):579–81. doi: 10.1038/ng1358.PubMedGoogle Scholar
  85. 85.
    Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, et al. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem. 2006;281(27):18370–7. doi: 10.1074/jbc.M602469200.PubMedGoogle Scholar
  86. 86.
    Frishberg Y, Ito N, Rinat C, Yamazaki Y, Feinstein S, Urakawa I, et al. Hyperostosis–hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J Bone Miner Res. 2007;22(2):235–42. doi: 10.1359/jbmr.061105.PubMedGoogle Scholar
  87. 87.
    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 Investig. 2007;117(9):2684–91.PubMedGoogle Scholar
  88. 88.
    Weber TJ, Liu S, Indridason OS, Quarles LD. Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res. 2003;18(7):1227–34. doi: 10.1359/jbmr.2003.18.7.1227.PubMedGoogle Scholar
  89. 89.
    Shigematsu T, Kazama JJ, Yamashita T, Fukumoto S, Hosoya T, Gejyo F, et al. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis. 2004;44(2):250–6. doi: 10.1053/j.ajkd.2004.04.029.PubMedGoogle Scholar
  90. 90.
    Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, et al. Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem. 2005;280(4):2543–9.PubMedGoogle Scholar
  91. 91.
    Ferrari SL, Bonjour JP, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab. 2005;90(3):1519–24. doi: 10.1210/jc.2004-1039.PubMedGoogle Scholar
  92. 92.
    Yu X, Sabbagh Y, Davis SI, Demay MB, White KE. Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations. Bone. 2005;36(6):971–7. doi: 10.1016/j.bone.2005.03.002.PubMedGoogle Scholar
  93. 93.
    Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res. 2006;21(8):1187–96. doi: 10.1359/jbmr.060507.PubMedGoogle Scholar
  94. 94.
    Ito N, Findlay DM, Anderson PH, Bonewald LF, Atkins GJ. Extracellular phosphate modulates the effect of 1alpha,25-dihydroxy vitamin D(3) (1,25D) on osteocyte like cells. J Steroid Biochem Mol Biol. 2012;. doi: 10.1016/j.jsbmb.2012.09.029.PubMedGoogle Scholar
  95. 95.
    Yamamoto R, Minamizaki T, Yoshiko Y, Yoshioka H, Tanne K, Aubin JE, et al. 1alpha,25-Dihydroxyvitamin D3 acts predominately in mature osteoblasts under conditions of high extracellular phosphate to increase fibroblast growth factor 23 production in vitro. J Endocrinol. 2010;206(3):279–86. doi: 10.1677/JOE-10-0058.PubMedCentralPubMedGoogle Scholar
  96. 96.
    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(6):G1036–42.PubMedGoogle Scholar
  97. 97.
    Ito M, Sakai Y, Furumoto M, Segawa H, Haito S, Yamanaka S, et al. Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells. Am J Physiol Endocrinol Metab. 2005;288(6):E1101–9. doi: 10.1152/ajpendo.00502.2004.PubMedGoogle Scholar
  98. 98.
    Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol. 2006;17(5):1305–15.PubMedGoogle Scholar
  99. 99.
    Chefetz I, Kohno K, Izumi H, Uitto J, Richard G, Sprecher E. GALNT3, a gene associated with hyperphosphatemic familial tumoral calcinosis, is transcriptionally regulated by extracellular phosphate and modulates matrix metalloproteinase activity. Biochim Biophys Acta. 2009;1792(1):61–7. doi: 10.1016/j.bbadis.2008.09.016.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Bhattacharyya N, Wiench M, Dumitrescu C, Connolly BM, Bugge TH, Patel HV, et al. Mechanism of FGF23 processing in fibrous dysplasia. J Bone Miner Res. 2012;. doi: 10.1002/jbmr.1546.Google Scholar
  101. 101.
    Ohata Y, Arahori H, Namba N, Kitaoka T, Hirai H, Wada K, et al. Circulating levels of soluble alpha-Klotho are markedly elevated in human umbilical cord blood. J Clin Endocrinol Metab. 2011;96(6):E943–7. doi: 10.1210/jc.2010-2357.PubMedGoogle Scholar
  102. 102.
    Heipertz R, Eickhoff K, Karstens KH. Magnesium and inorganic phosphate content in CSF related to blood–brain barrier function in neurological disease. J Neurol Sci. 1979;40(2–3):87–95.PubMedGoogle Scholar
  103. 103.
    Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Investig. 2007;117(12):4003–8. doi: 10.1172/JCI32409.PubMedGoogle Scholar
  104. 104.
    Isakova T, Wahl P, Vargas GS, Gutierrez OM, Scialla J, Xie H, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 2011;79(12):1370–8. doi: 10.1038/ki.2011.47.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Huang QL, Feig DS, Blackstein ME. Development of tertiary hyperparathyroidism after phosphate supplementation in oncogenic osteomalacia. J Endocrinol Investig. 2000;23(4):263–7.Google Scholar
  106. 106.
    Galitzer H, Ben-Dov IZ, Silver J, Naveh-Many T. Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int. 2010;77(3):211–8. doi: 10.1038/ki.2009.464.PubMedGoogle Scholar
  107. 107.
    Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol. 2005;16(7):2205–15. doi: 10.1681/ASN.2005010052.PubMedGoogle Scholar
  108. 108.
    Isakova T, Gutierrez O, Shah A, Castaldo L, Holmes J, Lee H, et al. Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol. 2008;19(3):615–23. doi: 10.1681/ASN.2007060673.PubMedGoogle Scholar
  109. 109.
    Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359(6):584–92. doi: 10.1056/NEJMoa0706130.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Shalhoub V, Shatzen EM, Ward SC, Davis J, Stevens J, Bi V, et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J Clin Investig. 2012;122(7):2543–53. doi: 10.1172/JCI61405.PubMedGoogle Scholar
  111. 111.
    Evenepoel P, Naesens M, Claes K, Kuypers D, Vanrenterghem Y. Tertiary ‘hyperphosphatoninism’ accentuates hypophosphatemia and suppresses calcitriol levels in renal transplant recipients. Am J Transplant. 2007;7(5):1193–200. doi: 10.1111/j.1600-6143.2007.01753.x.PubMedGoogle Scholar
  112. 112.
    Kawarazaki H, Shibagaki Y, Fukumoto S, Kido R, Nakajima I, Fuchinoue S, et al. The relative role of fibroblast growth factor 23 and parathyroid hormone in predicting future hypophosphatemia and hypercalcemia after living donor kidney transplantation: a 1-year prospective observational study. Nephrol Dial Transplant. 2011;26(8):2691–5. doi: 10.1093/ndt/gfq777.PubMedGoogle Scholar
  113. 113.
    Kazama JJ, Sato F, Omori K, Hama H, Yamamoto S, Maruyama H, et al. Pretreatment serum FGF-23 levels predict the efficacy of calcitriol therapy in dialysis patients. Kidney Int. 2005;67(3):1120–5. doi: 10.1111/j.1523-1755.2005.00178.x.PubMedGoogle Scholar
  114. 114.
    Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119(19):2545–52. doi: 10.1161/CIRCULATIONAHA.108.844506.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Mirza MA, Larsson A, Melhus H, Lind L, Larsson TE. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis. 2009;207(2):546–51. doi: 10.1016/j.atherosclerosis.2009.05.013.PubMedGoogle Scholar
  116. 116.
    Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. J Clin Investig. 2011;121(11):4393–408. doi: 10.1172/JCI46122.PubMedGoogle Scholar
  117. 117.
    Mirza MA, Larsson A, Lind L, Larsson TE. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis. 2009;205(2):385–90. doi: 10.1016/j.atherosclerosis.2009.01.001.PubMedGoogle Scholar
  118. 118.
    Scialla JJ, Lau WL, Reilly MP, Isakova T, Yang HY, Crouthamel MH, et al. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int. 2013;. doi: 10.1038/ki.2013.3.Google Scholar
  119. 119.
    Lindberg K, Olauson H, Amin R, Ponnusamy A, Goetz R, Taylor RF, et al. Arterial Klotho expression and FGF23 effects on vascular calcification and function. PLoS One. 2013;8(4):e60658. doi: 10.1371/journal.pone.0060658.PubMedCentralPubMedGoogle Scholar
  120. 120.
    Potts JT. Parathyroid hormone: past and present. J Endocrinol. 2005;187(3):311–25. doi: 10.1677/joe.1.06057.PubMedGoogle Scholar
  121. 121.
    Juppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991;254(5034):1024–6.PubMedGoogle Scholar
  122. 122.
    Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature. 1993;366(6455):575–80. doi: 10.1038/366575a0.PubMedGoogle Scholar
  123. 123.
    Kumar R, Thompson JR. The regulation of parathyroid hormone secretion and synthesis. J Am Soc Nephrol. 2011;22(2):216–24. doi: 10.1681/ASN.2010020186.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Nobuaki Ito
    • 1
  • David M. Findlay
    • 1
  • Gerald J. Atkins
    • 1
    Email author
  1. 1.Bone Cell Biology Group, Centre for Orthopaedic and Trauma ResearchThe University of AdelaideNorth Terrace, AdelaideAustralia

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