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X-linked hypophosphatemia and growth

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A Correction to this article was published on 07 November 2017

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Abstract

X-Linked hypophosphatemia (XLH) is the most common form of hereditary rickets caused by loss-of function mutations in the PHEX gene. XLH is characterized by hypophosphatemia secondary to renal phosphate wasting, inappropriately low concentrations of 1,25 dihydroxyvitamin D and high circulating levels of fibroblast growth factor 23 (FGF23). Short stature and rachitic osseous lesions are characteristic phenotypic findings of XLH although the severity of these manifestations is highly variable among patients. The degree of growth impairment is not dependent on the magnitude of hypophosphatemia or the extent of legs´ bowing and height is not normalized by chronic administration of phosphate supplements and 1α hydroxyvitamin D derivatives. Treatment with growth hormone accelerates longitudinal growth rate but there is still controversy regarding the potential risk of increasing bone deformities and body disproportion. Treatments aimed at blocking FGF23 action are promising, but information is lacking on the consequences of counteracting FGF23 during the growing period. This review summarizes current knowledge on phosphorus metabolism in XLH, presents updated information on XLH and growth, including the effects of FGF23 on epiphyseal growth plate of the Hyp mouse, an animal model of the disease, and discusses growth hormone and novel FGF23 related therapies.

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Change history

  • 07 November 2017

    The authors of the article would like to note an error in the acknowledgements section of this paper.

  • 07 November 2017

    The authors of the article would like to note an error in the acknowledgements section of this paper.

  • 07 November 2017

    The authors of the article would like to note an error in the acknowledgements section of this paper.

References

  1. Santos F, Fuente R, Mejia N, Mantecon L, Gil-Peña H, Ordoñez FA. Hypophosphatemia and growth. Pediatric Nephrology. 2013;28:595–603.

    Article  PubMed  Google Scholar 

  2. Wagner CA, Rubio-Aliaga I, Biber J, Hernando N. Genetic diseases of renal phosphate handling. Nephrol Dial Transplant England. 2014;29:45–54.

    Article  Google Scholar 

  3. Biber J, Stieger B, Stange G, Murer H. Isolation of renal proximal tubular brush-border membranes. Nature Protocols England. 2007;2:1356–9.

    Article  CAS  Google Scholar 

  4. Marks J, Debnam ES, Unwin RJ. Phosphate homeostasis and the renal-gastrointestinal axis. American Journal of Physiology. Renal Physiology. 2010;299:285–96.

    Article  Google Scholar 

  5. Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, Biber J, Forster IC. The Na + −pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary pi. American Journal of Physiology. Renal Physiology. 2009;296:691–9.

    Article  Google Scholar 

  6. Forster IC, Hernando N, Biber J, Murer H. Proximal tubular handling of phosphate: a molecular perspective. Kidney International. 2006;70:1548–59.

    Article  CAS  PubMed  Google Scholar 

  7. Brenza HL, Kimmel-Jehan C, Jehan F, Shinki T, Wakino S, Anazawa H, Suda T, DeLuca HF. Parathyroid hormone activation of the 25-hydroxyvitamin D3-1alpha-hydroxylase gene promoter. Proceedings of the National Academy of Sciences. 1998;95:1387–91.

    Article  CAS  Google Scholar 

  8. Kogawa M, Findlay DM, Anderson PH, Ormsby R, Vincent C, Morris HA, Atkins GJ. Osteoclastic metabolism of 25(OH)-vitamin D3: a potential mechanism for optimization of bone resorption. Endocrinology. 2010;151:4613–25.

    Article  CAS  PubMed  Google Scholar 

  9. Liu S, Zhou J, Tang W, Menard R, Feng JQ, Quarles LD. Pathogenic role of Fgf23 in Dmp1-null mice. American Journal of Physiology. Endocrinology and Metabolism. 2008;295:E254–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ubaidus S, Li M, Sultana S, de Freitas PHL, Oda K, Maeda T, Takagi R, Amizuka N. FGF23 is mainly synthesized by osteocytes in the regularly distributed osteocytic lacunar canalicular system established after physiological bone remodeling. Journal of Electron Microscopy. 2009;58:381–92.

    Article  CAS  PubMed  Google Scholar 

  11. Quarles LD. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nature Reviews. Endocrinology. 2012;8:276–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, Jüppner H, Jonsson KB. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology. 2004;145:3087–94.

    Article  CAS  PubMed  Google Scholar 

  13. Martin A, David V, Quarles LD. Regulation and Function of the FGF23/Klotho Endocrine Pathways. Physiological Reviews. 2012;92:131–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770–4.

    Article  CAS  PubMed  Google Scholar 

  15. Toro CL. Rol de Klotho y FGF23 en la regulación de fosfato y calcio plasmático. Rev Hosp Clin Univ Chile. 2010;23:25–32.

    Google Scholar 

  16. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M. Regulation of fibroblast growth factor-23 signaling by klotho. The Journal of Biological Chemistry. 2006;281:6120–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Farrow EG, Summers LJ, Schiavi SC, McCormick JA, Ellison DH, White KE. Altered renal FGF23-mediated activity involving MAPK and Wnt: effects of the hyp mutation. The Journal of Endocrinology. 2010;207:67–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Review of Development Biology. 2015;4:215–66.

    CAS  Google Scholar 

  19. Sopjani M, Rinnerthaler M, Almilaji A, Ahmeti S, Dermaku-Sopjani M. Regulation of cellular transport by klotho protein. Current Protein & Peptide Science. 2014;15:828–35.

    Article  CAS  Google Scholar 

  20. Razzaque MS. The FGF23-klotho axis: endocrine regulation of phosphate homeostasis. Nature Reviews. Endocrinology. 2009;5:611–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Webster R, Sheriff S, Faroqui R, Siddiqui F, Hawse JR, Amlal H. Klotho/fibroblast growth factor 23- and PTH-independent estrogen receptor-alpha-mediated direct downregulation of NaPi-IIa by estrogen in the mouse kidney. American Journal of Physiology. Renal Physiology. 2016;311:F249–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dermaku-Sopjani M, Sopjani M, Saxena A, Shojaiefard M, Bogatikov E, Alesutan I, Eichenmüller M, Lang F. Downregulation of NaPi-IIa and NaPi-IIb Na-coupled phosphate transporters by coexpression of klotho. Cellular Physiology and Biochemistry. 2011;28:251–8.

    Article  CAS  PubMed  Google Scholar 

  23. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y. Alpha-klotho as a regulator of calcium homeostasis. Science. 2007;316:1615–8.

    Article  CAS  PubMed  Google Scholar 

  24. Chang Q, Hoefs S, Van Der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science. 2005;310:490–3.

    Article  CAS  PubMed  Google Scholar 

  25. Andrukhova O, Smorodchenko A, Egerbacher M, Streicher C, Zeitz U, Goetz R, Shalhoub V, Mohammadi M, Pohl EE, Lanske B, Erben RG. FGF23 promotes renal calcium reabsorption through the TRPV5 channel. The EMBO Journal. 2014;33(3):229–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Burnett CH, Dent CE, Harper C, Warland BJ. Vitamin d-resistant rickets. Analysis of twenty-four pedigrees with hereditary and sporadic cases. The American Journal of Medicine. 1964;36:222–32.

    Article  CAS  PubMed  Google Scholar 

  27. Ramussen H, Anast C. Familial hypophosphatemic rickets and vitamin D-dependent rickets. In: Wyngaarden JB, Fredericson DS, Goldstain JL, Brrown MS, editors. The Metabolic Basis of Inherit Disease. N Y: McGraw-Hill; 1983. p. 1743–73.

    Google Scholar 

  28. Collins JF, Bulus N, Ghishan FK. Sodium-phosphate transporter adaptation to dietary phosphate deprivation in normal and hypophosphatemic mice. American Journal of Physics. 1995;268:917–24.

    Google Scholar 

  29. Eicher EM, Southard JL, Scriver CR, Glorieux FH. Hypophosphatemia - mouse model for human familial hypophosphatemic (vitamin-D-resistant) rickets. Proceedings of the National Academy of Sciences. 1976;73:4667–71.

    Article  CAS  Google Scholar 

  30. Strom TM, Francis F, Lorenz B, Böddrich A, Econs MJ, Lehrach H, Meitinger T. Pex gene deletions in Gy and hyp mice provide mouse models for X-linked hypophosphatemia. Human Molecular Genetics. 1997;6:165–71.

    Article  CAS  PubMed  Google Scholar 

  31. Tenenhouse H. X-linked hypophosphataemia: a homologous disorder in humans and mice. Nephrology, Dialysis, Transplantation. 1999;333–41

  32. Tenenhouse HS, Beck L. Renal Na + −phosphate cotransporter gene expression in X-linked hyp and Gy mice. Kidney International. 1996;49:1027–32.

    Article  CAS  PubMed  Google Scholar 

  33. Razali NN, Hwu TT, Thilakavathy K. Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets. Journal of Pediatric Endocrinology & Metabolism. 2015;28:1009–17.

    Article  CAS  Google Scholar 

  34. The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nature Genetics. 1995;11:130–6.

    Article  Google Scholar 

  35. Dixon PH, Christie PT, Wooding C, Trump D, Grieff M, Holm I, Gertner JM, Schmidtke J, Shah B, Shaw N, Smith C, Tau C, Schlessinger D, Whyte MP, Thakker RV. Mutational analysis of PHEX Gene in X-liked hypophosphatemia. The Journal of Clinical Endocrinology and Metabolism. 2014;83:3615–23.

    Google Scholar 

  36. Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, Tenenhouse HS. Pex/PEX tissue distribution and evidence for a deletion in the 3′ region of the Pex gene in X-linked hypophosphatemic mice. The Journal of Clinical Investigation. 1997;99:1200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bastepe M, Juppner H. Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation. Reviews in Endocrine & Metabolic Disorders. 2008;9:171–80.

    Article  Google Scholar 

  38. Meyer RAJ, Tenenhouse HS, Meyer MH, Klugerman AH. The renal phosphate transport defect in normal mice parabiosed to X-linked hypophosphatemic mice persists after parathyroidectomy. Journal of Bone and Mineral Research. 1989;4:523–32.

    Article  CAS  PubMed  Google Scholar 

  39. Tenenhouse HS, Martel J, Gauthier C, Segawa H, Miyamoto K. Differential effects of Npt2a gene ablation and X-linked hyp mutation on renal expression of Npt2c. American Journal of Physiology. Renal Physiology. 2003;285:1271–8.

    Article  Google Scholar 

  40. Liu S, Tang W, Zhou J, Vierthaler L, Quarles LD. Distinct roles for intrinsic osteocyte abnormalities and systemic factors in regulation of FGF23 and bone mineralization in hyp mice. American Journal of Physiology. Endocrinology and Metabolism. 2007;293:1636–44.

    Article  Google Scholar 

  41. Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. The Journal of Clinical Endocrinology and Metabolism. 2002;87:4957–60.

    Article  CAS  PubMed  Google Scholar 

  42. Chanakul A, Zhang MY, Louw A, Armbrecht HJ, Miller WL, Portale AA, Perwad F. FGF-23 regulates CYP27B1 transcription in the kidney and in extra-renal tissues. PLoS One. 2013;8:72816.

    Article  Google Scholar 

  43. Reid IR, Murphy WA, Hardy DC, Teitelbaum SL, Bergfeld MA, Whyte MP. X-linked hypophosphatemia: skeletal mass in adults assessed by histomorphometry, computed tomography, and absorptiometry. The American Journal of Medicine. 1991;90:63–9.

    Article  CAS  PubMed  Google Scholar 

  44. Klaus SSB, Lars B. Phenotype presentation of hypophosphatemic rickets in adults. Calcified Tissue International. 2010;87:108–19.

    Article  Google Scholar 

  45. Weber TJ, Liu S, Indridason OS, Quarles LD. Serum FGF23 levels in normal and disordered phosphorus homeostasis. Journal of Bone and Mineral Research. 2003;18:1227–34.

    Article  CAS  PubMed  Google Scholar 

  46. Schutt SM, Schumacher M, Holterhus PM, Felgenhauer S, Hiort O. Effect of GH replacement therapy in two male siblings with combined X-linked hypophosphatemia and partial GH deficiency. European Journal of Endocrinology. 2003;149:317–21.

    Article  PubMed  Google Scholar 

  47. Mäkitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. The Journal of Clinical Endocrinology and Metabolism. 2003;88:3591–7.

    Article  PubMed  Google Scholar 

  48. Baroncelli GI, Bertelloni S, Ceccarelli C, Saggese G. Effect of growth hormone treatment on final height, phosphate metabolism, and bone mineral density in children with X-linked hypophosphatemic rickets. The Journal of Pediatrics. 2001;138:236–43.

    Article  CAS  PubMed  Google Scholar 

  49. Whyte MP, Schranck FW, Armamento-Villareal R. X-linked hypophosphatemia: a search for gender, race, anticipation, or parent of origin effects on disease expression in children. The Journal of Clinical Endocrinology and Metabolism. 1996;81:4075–80.

    CAS  PubMed  Google Scholar 

  50. Živičnjak M, Schnabel D, Billing H, Staude H, Filler G, Querfeld U, Schumacher M, Pyper A, Schröder C, Brämswig J, Haffner D. Hypophosphatemic Rickets Study Group of Arbeitsgemeinschaft für Pädiatrische Endokrinologie and Gesellschaft für Pädiatrische Nephrologie. Age-related stature and linear body segments in children with X-linked hypophosphatemic rickets. Pediatric Nephrology. 2011;26:223–31.

    Article  PubMed  Google Scholar 

  51. Linglart A, Biosse-Duplan M, Briot K, Chaussain C, Esterle L, Guillaume-Czitrom S, Kamenicky P, Nevoux J, Prié D, Rothenbuhler A, Wicart P, Harvengt P. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocrine Connections. 2014;3:13–30.

    Article  Google Scholar 

  52. Jehan F, Gaucher C, Nguyen TM, Walrant-Debray O, Lahlou N, Sinding C, Déchaux M, Garabédian M. Vitamin D receptor genotype in hypophosphatemic rickets as a predictor of growth and response to treatment. The Journal of Clinical Endocrinology and Metabolism. 2008;93:4672–82.

    Article  CAS  PubMed  Google Scholar 

  53. McNair, Stickler. Growth in familial hypophosphatemic vitamin-D-resistant rickets. NEJM. 1969;281:511–6.

    Article  Google Scholar 

  54. Oliveri MB, Cassinelli H, Bergada C, Mautalen CA. Bone mineral density of the spine and radius shaft in children with X-linked hypophosphatemic rickets (XLH). Bone and Mineral. 1991;12:91–100.

    Article  CAS  PubMed  Google Scholar 

  55. Friedman NE, Lobaugh B, Drezner MK. Effects of calcitriol and phosphorus therapy on the growth of patients with X-linked hypophosphatemia. The Journal of Clinical Endocrinology and Metabolism. 1993;76:839–44.

    CAS  PubMed  Google Scholar 

  56. Qiu ZQ, Travers R, Rauch F, Glorieux FH, Scriver CR, Tenenhouse HS. Effect of gene dose and parental origin on bone histomorphometry in X-linked hyp mice. Bone. 2004;34:134–9.

    Article  CAS  PubMed  Google Scholar 

  57. Hunziker EB. Mechanism of longitudinal bone growth and its regulation by growth plate chondrocytes. Microscopy Research and Technique. 1994;28:505–19.

    Article  CAS  PubMed  Google Scholar 

  58. Liu S, Guo R, Quarles LD. Cloning and characterization of the proximal murine Phex promoter. Endocrinology. 2001;142:3987–95.

    Article  CAS  PubMed  Google Scholar 

  59. Miao D, Bai X, Panda D, McKee M, Karaplis A, Goltzman D. Osteomalacia in hyp mice is associated with abnormal Phex expression and with altered bone matrix protein expression and deposition. Endocrinology. 2001;142:926–39.

    Article  CAS  PubMed  Google Scholar 

  60. Miao D, Bai X, Panda DK, Karaplis AC, Goltzman D, McKee MD. Cartilage abnormalities are associated with abnormal Phex expression and with altered matrix protein and MMP-9 localization in hyp mice. Bone. 2004;34:638–47.

    Article  CAS  PubMed  Google Scholar 

  61. Wu S, Levenson A, Kharitonenkov A, De Luca F. Fibroblast growth factor 21 (FGF21) inhibits chondrocyte function and growth hormone action directly at the growth plate. The Journal of Biological Chemistry. 2012;287:26060–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gunther T, Chen Z-F, Kim J, Priemel M, Rueger JM, Amling M, Moseley JM, Martin TJ, Anderson DJ, Karsenty G. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature. 2000;406:199–203.

    Article  CAS  PubMed  Google Scholar 

  63. Tu Q, Pi M, Karsenty G, Simpson L, Liu S, Quarles LD. Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. The Journal of Clinical Investigation. 2003;111:1029–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sabbagh Y, Carpenter TO, Demay MB. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proceedings of the National Academy of Sciences. 2005;102:9637–42.

    Article  CAS  Google Scholar 

  65. Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD. Pathogenic role of Fgf23 in hyp mice. American Journal of Physiology. Endocrinology and Metabolism. 2006;291:38–49.

    Article  Google Scholar 

  66. Ovejero D, Lim YH, Boyce AM, Gafni RI, McCarthy E, Nguyen TA, Eichenfield LF, DeKlotz CM, Guthrie LC, Tosi LL, Thornton PS, Choate KA, Collins MT. Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment. Osteoporosis International. 2016;27:3615–26.

    Article  CAS  PubMed  Google Scholar 

  67. Goodyer PR, Kronick JB, Jequier S, Reade TM, Scriver CR. Nephrocalcinosis and its relationship to treatment of hereditary rickets. The Journal of Pediatrics. 1987;111:700–4.

    Article  CAS  PubMed  Google Scholar 

  68. Sanchez CP. Mineral metabolism and bone abnormalities in children with chronic renal failure. Reviews in Endocrine & Metabolic Disorders. 2008;9:131–7.

    Article  CAS  Google Scholar 

  69. Imel EA, DiMeglio LA, Hui SL, Carpenter TO, Econs MJ. Treatment of X-linked hypophosphatemia with calcitriol and phosphate increases circulating fibroblast growth factor 23 concentrations. The Journal of Clinical Endocrinology and Metabolism. 2010;95:1846–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nickolas TL, Jamal SA. Bone kidney interactions. Reviews in Endocrine & Metabolic Disorders. 2015;16:157–63.

    Article  CAS  Google Scholar 

  71. Wilson DM, Lee PD, Morris AH, Reiter EO, Gertner JM, Marcus R, Valerie E. Ron G. Growth hormone therapy in hypophosphatemic rickets. American Journal of Diseases of Children (1911). 1991;145:1165–70.

    CAS  Google Scholar 

  72. Cameron FJ, Sochett EB, Daneman A, Kooh SW. A trial of growth hormone therapy in well-controlled hypophosphataemic rickets. Clinical Endocrinology. 1999;50:577–82.

    Article  CAS  PubMed  Google Scholar 

  73. Haffner D, Nissel R, Wuhl E, Mehls O. Effects of growth hormone treatment on body proportions and final height among small children with X-linked hypophosphatemic rickets. Pediatrics. 2004;113:593–6.

    Article  Google Scholar 

  74. Roy P, Martel J, Tenenhouse H. Growth hormone normalizes renal 1,25-dihydroxyvitamin D3-24-hydroxylase gene expression but not Na + −phosphate cotransporter (Npt2) mRNA in phosphate-deprived hyp mice. Journal of Bone and Mineral Research. 1997;12:1672–80.

    Article  CAS  PubMed  Google Scholar 

  75. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:6500–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney International. 2001;60:2079–86.

    Article  CAS  PubMed  Google Scholar 

  77. Wöhrle S, Bonny O, Beluch N, Gaulis S, Stamm C, Scheibler M, Müller M, Kinzel B, Thuery A, Brueggen J, Hynes NE, Sellers WR, Hofmann F, Graus-Porta D. FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. Journal of Bone and Mineral Research. 2011;26:2486–97.

    Article  PubMed  Google Scholar 

  78. Li H, Martin A, David V, Quarles LD. Compound deletion of Fgfr3 and Fgfr4 partially rescues the hyp mouse phenotype. American Journal of Physiology. Endocrinology and Metabolism. 2011;300:508–17.

    Article  Google Scholar 

  79. Bai X, Miao D, Xiao S, Qiu D, St-Arnaud R, Petkovich M, Gupta A, Goltzman D, Karaplis AC. CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders. The Journal of Clinical Investigation. 2016;126:667–80.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wöhrle S, Henninger C, Bonny O, Thuery A, Beluch N, Hynes NE, Guagnano V, Sellers WR, Hofmann F, Kneissel M, Graus PD. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. Journal of Bone and Mineral Research. 2013;28:899–911.

    Article  PubMed  Google Scholar 

  81. Du E, Xiao L, Hurley MM. FGF23 neutralizing antibody ameliorates hypophosphatemia and impaired FGF receptor signaling in kidneys of HMWFGF2 transgenic mice. Journal of Cellular Physiology. 2016; doi:10.1002/jcp.25458.

    Google Scholar 

  82. Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, Fujita T, Wada M, Yamashita T, Fukumoto S, Shimada T. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. Journal of Bone and Mineral Research. 2009;24:1879–88.

    Article  CAS  PubMed  Google Scholar 

  83. Ranch D, Zhang MYH, Portale AA, Perwad F. Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in hyp mice. Journal of Bone and Mineral Research. 2011;26:1883–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhang MYH, Ranch D, Pereira RC, Armbrecht HJ, Portale AA, Perwad F. Chronic inhibition of ERK1/2 signaling improves disordered bone and mineral metabolism in hypophosphatemic (hyp) mice. Endocrinology. 2012;153:1806–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T, Vergeire M, Humphrey JS, Glorieux FH, Portale AA, Insogna K, Peacock M, Carpenter TO. Prolonged correction of serum phosphorus in adults with X-linked hypophosphatemia using monthly doses of KRN23. The Journal of Clinical Endocrinology and Metabolism. 2015;100:2565–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, Kawakami T, Ito T, Zhang X, Humphrey J, Insogna KL, Peacock M. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. The Journal of Clinical Investigation. 2014;124:1587–97.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Plan I + D + I 2008-2011, Instituto de Salud Carlos III (PI12/00987) and also by the National Plan I + D + I 2013-2016 Instituto de Salud Carlos III (PI14/00702 and PI15/02122), European Regional Development Funds 2013-2016 (ERDF, Grupín 14-020) and by the Foundation of the University of Oviedo (FUO).

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  1. Division of Pediatrics, Department of Medicine. Faculty of Medicine, University of Oviedo, Oviedo, Asturias, Spain

    R. Fuente, D. Claramunt-Taberner, O. Hernández, A. Fernández-Iglesias, L. Alonso-Durán, E. Rodríguez-Rubio & F. Santos

  2. Department of Pediatrics, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain

    H. Gil-Peña & F. Santos

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Fuente, R., Gil-Peña, H., Claramunt-Taberner, D. et al. X-linked hypophosphatemia and growth. Rev Endocr Metab Disord 18, 107–115 (2017). https://doi.org/10.1007/s11154-017-9408-1

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  • DOI: https://doi.org/10.1007/s11154-017-9408-1

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