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Current Molecular Biology Reports

, Volume 5, Issue 1, pp 34–47 | Cite as

Animal Models of Phosphorus Homeostasis

  • Laurent Beck
  • Despina SitaraEmail author
Molecular Control of Phosphorus Homeostasis (B van der Eerden, Section Editor)
  • 23 Downloads
Part of the following topical collections:
  1. Topical Collection on Molecular Control of Phosphorus Homeostasis

Abstract

Purpose of Review

Phosphate homeostasis is a complex process that involves many regulators and multiple organs. In vivo models have been used extensively to study the pathophysiological mechanisms of phosphate disorders. This review focuses on evaluating mouse models generated for the study of disorders of phosphate metabolism.

Recent Findings

Over the years, several mouse models have been generated by strategies that knockin or knockout one or more genes that encode for the phosphate transporters or other regulatory factors that directly or indirectly influence phosphate homeostasis. These models have shed light on the pathways involved in phosphate metabolism and the mechanisms that lead to phosphate dysregulation in human diseases.

Summary

Animal models are essential tools to study multisystem disorders that affect multiple organs and cell types. In particular, mouse models generated by a variety of genetic approaches have become the preferred mammalian models to study human diseases. Mouse models of phosphate homeostasis have provided valuable insights and enhanced our understanding of the cross talk between bone, kidney, and intestine and the relationships between the key phosphate regulators FGF23, 1,25(OH)2-vitamin D3, and PTH.

Keywords

Phosphorus homeostasis Animal models FGF23 Kidney Bone Mineralization 

Notes

Compliance with Ethical Standards

Conflict of Interest

Laurent Beck and Despina Sitara each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

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

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Khoshniat S, Bourgine A, Julien M, Weiss P, Guicheux J, Beck L. The emergence of phosphate as a specific signaling molecule in bone and other cell types in mammals. Cell Mol Life Sci. 2011;68(2):205–18.PubMedGoogle Scholar
  2. 2.
    Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci. 1998;95(9):5372–7.PubMedGoogle Scholar
  3. 3.
    Ohi A, Hanabusa E, Ueda O, Segawa H, Horiba N, Kaneko I, et al. Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b(+)/(-) mice. Am J Physiol Ren Physiol. 2011;301(5):F1105–13.Google Scholar
  4. 4.
    Segawa H, Onitsuka A, Furutani J, Kaneko I, Aranami F, Matsumoto N, et al. Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development. AJP: Renal Physiol. 2009;297(3):F671–8.Google Scholar
  5. 5.
    Segawa H, Onitsuka A, Kuwahata M, Hanabusa E, Furutani J, Kaneko I, et al. Type IIc sodium-dependent phosphate transporter regulates calcium metabolism. J Am Soc Nephrol : JASN. 2009;20(1):104–13.PubMedGoogle Scholar
  6. 6.
    Shenolikar S, Voltz JW, Minkoff CM, Wade JB, Weinman EJ. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci U S A. 2002;99(17):11470–5.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Bai X, Miao D, Li J, Goltzman D, Karaplis AC. Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. Endocrinology. 2004;145(11):5269–79.PubMedGoogle Scholar
  8. 8.
    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(4):561–8.PubMedPubMedCentralGoogle Scholar
  9. 9.
    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.PubMedPubMedCentralGoogle Scholar
  10. 10.
    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 U S A. 2008;105(9):3455–60.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Ichikawa S, Sorenson AH, Austin AM, Mackenzie DS, Fritz TA, Moh A, et al. Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression. Endocrinology. 2009;150(6):2543–50.PubMedPubMedCentralGoogle Scholar
  12. 12.
    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.PubMedPubMedCentralGoogle Scholar
  13. 13.
    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.PubMedGoogle Scholar
  14. 14.
    Yuan Q, Sato T, Densmore M, Saito H, Schuler C, Erben RG, et al. Deletion of PTH rescues skeletal abnormalities and high osteopontin levels in Klotho-/- mice. PLoS Genet. 2012;8(5):e1002726.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, et al. Pex/PEX tissue distribution and evidence for a deletion in the 3' region of the Pex gene in X-linked hypophosphatemic mice. J Clin Invest. 1997;99(6):1200–9.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Eicher EM, Southard JL, Scriver CR, Glorieux FH. Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets. Proc Natl Acad Sci. 1976;73(12):4667–71.PubMedGoogle Scholar
  17. 17.
    Lyon MF, Scriver CR, Baker LR, Tenenhouse HS, Kronick J, Mandla S. The Gy mutation: another cause of X-linked hypophosphatemia in mouse. Proc Natl Acad Sci U S A. 1986;83(13):4899–903.PubMedPubMedCentralGoogle Scholar
  18. 18.
    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.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Strom TM, Francis F, Lorenz B, Boddrich A, Econs MJ, Lehrach H, et al. Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked hypophosphatemia. Hum Mol Genet. 1997;6(2):165–71.PubMedGoogle Scholar
  20. 20.
    Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 1998;19(3):271–3.PubMedGoogle Scholar
  21. 21.
    Panda DK, Miao D, Tremblay ML, Sirois J, Farookhi R, Hendy GN, et al. Targeted ablation of the 25-hydroxyvitamin D 1alpha -hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc Natl Acad Sci U S A. 2001;98(13):7498–503.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Dardenne O, Prud’homme J, Arabian A, Glorieux FH, St-Arnaud R. Targeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets. Endocrinology. 2001;142(7):3135–41.PubMedGoogle Scholar
  23. 23.
    Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci U S A. 1997;94(18):9831–5.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Gunther T, Chen ZF, Kim J, Priemel M, Rueger JM, Amling M, et al. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature. 2000;406(6792):199–203.PubMedGoogle Scholar
  25. 25.
    Miao D, He B, Karaplis AC, Goltzman D. Parathyroid hormone is essential for normal fetal bone formation. J Clin Invest. 2002;109(9):1173–82.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet. 1997;16(4):391–6.PubMedGoogle Scholar
  27. 27.
    Garner SC, Pi M, Tu Q, Quarles LD. Rickets in cation-sensing receptor-deficient mice: an unexpected skeletal phenotype. Endocrinology. 2001;142(9):3996–4005.PubMedGoogle Scholar
  28. 28.
    Ho C, Conner DA, Pollak MR, Ladd DJ, Kifor O, Warren HB, et al. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet. 1995;11(4):389–94.PubMedGoogle Scholar
  29. 29.
    Hough TA, Bogani D, Cheeseman MT, Favor J, Nesbit MA, Thakker RV, et al. Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification. Proc Natl Acad Sci U S A. 2004;101(37):13566–71.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Sakamoto A, Liu J, Greene A, Chen M, Weinstein LS. Tissue-specific imprinting of the G protein Gsalpha is associated with tissue-specific differences in histone methylation. Hum Mol Genet. 2004;13(8):819–28.PubMedGoogle Scholar
  31. 31.
    Beamer WG, Rosen CJ, Bronson RT, Gu W, Donahue LR, Baylink DJ, et al. Spontaneous fracture (sfx): a mouse genetic model of defective peripubertal bone formation. Bone. 2000;27(5):619–26.PubMedGoogle Scholar
  32. 32.
    Duan X, Liu J, Zheng X, Wang Z, Zhang Y, Hao Y, et al. Deficiency of ATP6V1H causes bone loss by inhibiting bone resorption and bone formation through the TGF-beta1 pathway. Theranostics. 2016;6(12):2183–95.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Li Q, Pratt CH, Dionne LA, Fairfield H, Karst SY, Sundberg JP, et al. Spontaneous asj-2J mutant mouse as a model for generalized arterial calcification of infancy: a large deletion/insertion mutation in the Enpp1 gene. PLoS One. 2014;9(12):e113542.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Marks SC Jr, Lane PW. Osteopetrosis, a new recessive skeletal mutation on chromosome 12 of the mouse. J Hered. 1976;67(1):11–8.PubMedGoogle Scholar
  35. 35.
    Yamamoto A, Takagi H, Kitamura D, Tatsuoka H, Nakano H, Kawano H, et al. Deficiency in protein L-isoaspartyl methyltransferase results in a fatal progressive epilepsy. J Neurosci. 1998;18(6):2063–74.PubMedGoogle Scholar
  36. 36.
    Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999;13(8):1015–24.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Vallon V, Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, et al. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011;22(1):104–12.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Hoenderop JGJ, van Leeuwen JPTM, van der Eerden BCJ, Kersten FFJ, van der Kemp AWCM, Mérillat A-M, et al. Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. J Clin Investig. 2003;112(12):1906–14.PubMedGoogle Scholar
  39. 39.
    Piwon N, Günther W, Schwake M, Bösl MR, Jentsch TJ. ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent’s disease. Nature. 2000;408(6810):369–73.PubMedGoogle Scholar
  40. 40.
    Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK, Wagenaar E, van Deemter L, et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell. 1993;75(3):451–62.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Odgren PR, Pratt CH, Mackay CA, Mason-Savas A, Curtain M, Shopland L, et al. Disheveled hair and ear (Dhe), a spontaneous mouse Lmna mutation modeling human laminopathies. PLoS One. 2010;5(4):e9959.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Wang SS, Devuyst O, Courtoy PJ, Wang XT, Wang H, Wang Y, et al. Mice lacking renal chloride channel, CLC-5, are a model for Dent’s disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis. Hum Mol Genet. 2000;9(20):2937–45.PubMedGoogle Scholar
  43. 43.
    Aqeilan RI, Trapasso F, Hussain S, Costinean S, Marshall D, Pekarsky Y, et al. Targeted deletion of Wwox reveals a tumor suppressor function. Proc Natl Acad Sci U S A. 2007;104(10):3949–54.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Bodine PV, Zhao W, Kharode YP, Bex FJ, Lambert AJ, Goad MB, et al. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol Endocrinol. 2004;18(5):1222–37.PubMedGoogle Scholar
  45. 45.
    Morgan WC. A new tail-short mutation in the mouse whose lethal effects are conditioned by the residual genotypes. J Hered. 1950;41(8):208–15.PubMedGoogle Scholar
  46. 46.
    Rosemann M, Ivashkevich A, Favor J, Dalke C, Holter SM, Becker L, et al. Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice. Mamm Genome. 2010;21(1–2):13–27.PubMedGoogle Scholar
  47. 47.
    Yadav MC, Simão AMS, Narisawa S, Huesa C, McKee MD, Farquharson C, et al. Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification. J Bone Miner Res. 2010;26(2):286–97.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Breiderhoff T, Himmerkus N, Stuiver M, Mutig K, Will C, Meij IC, et al. Deletion of claudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis. Proc Natl Acad Sci U S A. 2012;109(35):14241–6.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Harding B, Lemos MC, Reed AA, Walls GV, Jeyabalan J, Bowl MR, et al. Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Endocr Relat Cancer. 2009;16(4):1313–27.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Nie X, Arrighi I, Kaissling B, Pfaff I, Mann J, Barhanin J, et al. Expression and insights on function of potassium channel TWIK-1 in mouse kidney. Pflugers Arch. 2005;451(3):479–88.PubMedGoogle Scholar
  51. 51.
    Inaba M, Yawata A, Koshino I, Sato K, Takeuchi M, Takakuwa Y, et al. Defective anion transport and marked spherocytosis with membrane instability caused by hereditary total deficiency of red cell band 3 in cattle due to a nonsense mutation. J Clin Invest. 1996;97(8):1804–17.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Schumacher FR, Siew K, Zhang J, Johnson C, Wood N, Cleary SE, et al. Yasmin, et al. Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia. EMBO Mol Med. 2015;7(10):1285–306.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Shibazaki S, Yu Z, Nishio S, Tian X, Thomson RB, Mitobe M, et al. Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Hum Mol Genet. 2008;17(11):1505–16.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Moser M, Pscherer A, Roth C, Becker J, Mucher G, Zerres K, et al. Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta. Genes Dev. 1997;11(15):1938–48.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Peters LL, Shivdasani RA, Liu SC, Hanspal M, John KM, Gonzalez JM, et al. Anion exchanger 1 (band 3) is required to prevent erythrocyte membrane surface loss but not to form the membrane skeleton. Cell. 1996;86(6):917–27.PubMedGoogle Scholar
  56. 56.
    International Mouse Knockout C, Collins FS, Rossant J, Wurst W. A mouse for all reasons. Cell. 2007;128(1):9–13.Google Scholar
  57. 57.
    Magagnin S, Werner A, Markovich D, Sorribas V, Stange G, Biber J, et al. Expression cloning of human and rat renal cortex Na/Pi cotransport. Proc Natl Acad Sci. 1993;90(13):5979–83.PubMedGoogle Scholar
  58. 58.
    Tenenhouse HS, Werner A, Biber J, Ma S, Martel J, Roy S, et al. Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization. JClin Invest. 1994;93(2):671–6.Google Scholar
  59. 59.
    Kos CH, Tihy F, Econs MJ, Murer H, Lemieux N, Tenenhouse HS. Localization of a renal sodium-phosphate cotransporter gene to human chromosome 5q35. Genomics. 1994;19(1):176–7.PubMedGoogle Scholar
  60. 60.
    Perwad F, Azam N, Zhang MYH, 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.PubMedGoogle Scholar
  61. 61.
    Gupta A, Tenenhouse HS, Hoag HM, Wang D, Khadeer MA, Namba N, et al. Identification of the type II Na(+)-Pi cotransporter (Npt2) in the osteoclast and the skeletal phenotype of Npt2-/- mice. Bone. 2001;29(5):467–76.PubMedGoogle Scholar
  62. 62.
    Tenenhouse HS, Martel J, Gauthier C, Segawa H, Miyamoto K-I. Differential effects of Npt2a gene ablation and X-linked Hyp mutation on renal expression of Npt2c. Am J Physiol Ren Physiol. 2003;285(6):F1271–8.Google Scholar
  63. 63.
    Hoag HM, Martel J, Gauthier C, Tenenhouse HS. Effects of Npt2 gene ablation and low-phosphate diet on renal Na(+)/phosphate cotransport and cotransporter gene expression. J Clin Investig. 1999;104(6):679–86.PubMedGoogle Scholar
  64. 64.
    Zhao N, Tenenhouse HS. Npt2 gene disruption confers resistance to the inhibitory action of parathyroid hormone on renal sodium-phosphate cotransport. Endocrinology. 2000;141(6):2159–65.PubMedGoogle Scholar
  65. 65.
    Bourgeois S, Capuano P, Stange G, Muhlemann R, Murer H, Biber J, et al. The phosphate transporter NaPi-IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels. Pflugers Arch. 2013;465(11):1557–72.PubMedGoogle Scholar
  66. 66.
    Sitara D, Kim S, Razzaque MS, Bergwitz C, Taguchi T, Schüler C, et al. Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. PLoS Genet. 2008;4(8):e1000154.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Segawa H, Kaneko I, Takahashi A, Kuwahata M, Ito M, Ohkido I, et al. Growth-related renal type II Na/Pi cotransporter. J Biol Chem. 2002;277(22):19665–72.PubMedGoogle Scholar
  68. 68.
    Picard N, Capuano P, Stange G, Mihailova M, Kaissling B, Murer H, et al. Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters. Pflugers Arch. 2010;460(3):677–87.PubMedGoogle Scholar
  69. 69.
    Madjdpour C, Bacic D, Kaissling B, Murer H, Biber J. Segment-specific expression of sodium-phosphate cotransporters NaPi-IIa and -IIc and interacting proteins in mouse renal proximal tubules. Pflugers Arch. 2004;448(4):402–10.PubMedGoogle Scholar
  70. 70.
    Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, et al. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Genet. 2006;78(2):179–92.PubMedGoogle Scholar
  71. 71.
    Lorenz-Depiereux B, Benet-Pagès 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 Hum Genet. 2006;78(2):193–201.PubMedGoogle 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(10):611–7.PubMedGoogle Scholar
  73. 73.
    Myakala K, Motta S, Murer H, Wagner CA, Koesters R, Biber J, et al. Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice. AJP: Renal Physiol. 2014;306(8):F833–F43.Google Scholar
  74. 74.
    Murthy A, Gonzalez-Agosti C, Cordero E, Pinney D, Candia C, Solomon F, et al. NHE-RF, a regulatory cofactor for Na(+)-H+ exchange, is a common interactor for merlin and ERM (MERM) proteins. J Biol Chem. 1998;273(3):1273–6.PubMedGoogle Scholar
  75. 75.
    Capuano P, Bacic D, Roos M, Gisler SM, Stange G, Biber J, et al. Defective coupling of apical PTH receptors to phospholipase C prevents internalization of the Na +-phosphate cotransporter NaP i-IIa in Nherf1-deficient mice. AJP: Cell Physiology. 2007;292(2):C927–C34.Google Scholar
  76. 76.
    Hernando N, Déliot N, Gisler SM, Lederer E, Weinman EJ, Biber J, et al. PDZ-domain interactions and apical expression of type IIa Na/Pi cotransporters. Proc Natl Acad Sci U S A. 2002;99(18):11957–62.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Morales FC, Takahashi Y, Kreimann EL, Georgescu M-M. Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia. Proc Natl Acad Sci. 2004;101(51):17705–10.PubMedGoogle Scholar
  78. 78.
    Cunningham R, Xiaofei E, Steplock D, Shenolikar S, Weinman EJ. Defective PTH regulation of sodium-dependent phosphate transport in NHERF-1-/- renal proximal tubule cells and wild-type cells adapted to low-phosphate media. Am J Physiol Ren Physiol. 2005;289(4):F933–8.Google Scholar
  79. 79.
    Mahon MJ, Cole JA, Lederer ED, Segre GV. Na +/H +exchanger-regulatory factor 1 mediates inhibition of phosphate transport by parathyroid hormone and second messengers by acting at multiple sites in opossum kidney cells. Mol Endocrinol. 2003;17(11):2355–64.PubMedGoogle Scholar
  80. 80.
    Courbebaisse M, Leroy C, Bakouh N, Salaün C, Beck L, Grandchamp B, et al. A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism. PLoS One. 2012;7(4):e34764.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Karim Z, Gérard B, Bakouh N, Alili R, Leroy C, Beck L, et al. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med. 2008;359(11):1128–35.PubMedGoogle Scholar
  82. 82.
    Weinman EJ, Cunningham R, Wade JB, Shenolikar S. The role of NHERF-1 in the regulation of renal proximal tubule sodium-hydrogen exchanger 3 and sodium-dependent phosphate cotransporter 2a. J Physiol. 2005;567(1):27–32.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Villa-Bellosta R, Barac-Nieto M, Breusegem SY, Barry NP, Levi M, Sorribas V. Interactions of the growth-related, type IIc renal sodium/phosphate cotransporter with PDZ proteins. Kidney Int. 2008;73(4):456–64.PubMedGoogle Scholar
  84. 84.
    Mirams M, Robinson BG, Mason RS, Nelson AE. Bone as a source of FGF23: regulation by phosphate? Bone. 2004;35(5):1192–9.PubMedGoogle Scholar
  85. 85.
    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 U S A. 2001;98(11):6500–5.PubMedPubMedCentralGoogle Scholar
  86. 86.
    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.PubMedGoogle Scholar
  87. 87.
    Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol. 2013;75:503–33.PubMedPubMedCentralGoogle Scholar
  88. 88.
    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(10):6120–3.PubMedPubMedCentralGoogle Scholar
  89. 89.
    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.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393–408.PubMedPubMedCentralGoogle Scholar
  91. 91.
    • Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, et al. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab. 2015;22(6):1020–32 This study shows that mice lacking FGFR4 do not develop left ventricular hypertrophy (LVH) in response to elevated FGF23. However, whereas a gain-of-function mutation in FGFR4 results in development of LVH. Thus, FGF23 promotes LVH by activating FGFR4. PubMedPubMedCentralGoogle Scholar
  92. 92.
    •• Grabner A, Schramm K, Silswal N, Hendrix M, Yanucil C, Czaya B, et al. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Sci Rep. 2017;7(1):1993 This study shows that FGF23/FGFR4-induced cardiac hypertrophy can be reversed using and FGFR4 blocking antibody. PubMedPubMedCentralGoogle Scholar
  93. 93.
    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.PubMedGoogle Scholar
  94. 94.
    Consortium A. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26(3):345–8.Google Scholar
  95. 95.
    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.PubMedGoogle Scholar
  96. 96.
    Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, et al. 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(7):3087–94.PubMedGoogle Scholar
  97. 97.
    Hesse M, Frohlich LF, Zeitz U, Lanske B, Erben RG. Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol. 2007;26(2):75–84.PubMedGoogle Scholar
  98. 98.
    Sitara D, Razzaque MS, St-Arnaud R, Huang W, Taguchi T, Erben RG, et al. Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals. Am J Pathol. 2006;169(6):2161–70.PubMedPubMedCentralGoogle Scholar
  99. 99.
    DeLuca S, Sitara D, Kang K, Marsell R, Jonsson K, Taguchi T, et al. Amelioration of the premature ageing-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-23. J Pathol. 2008;216(3):345–55.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun. 1998;242(3):626–30.PubMedGoogle Scholar
  101. 101.
    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(9):2684–91.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Nakatani T, Sarraj B, Ohnishi M, Densmore MJ, Taguchi T, Goetz R, et al. In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) -mediated regulation of systemic phosphate homeostasis. FASEB J. 2009;23(2):433–41.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Anour R, Andrukhova O, Ritter E, Zeitz U, Erben RG. Klotho lacks a vitamin D independent physiological role in glucose homeostasis, bone turnover, and steady-state PTH secretion in vivo. PLoS One. 2012;7(2):e31376.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Ohnishi M, Nakatani T, Lanske B, Razzaque MS. Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase. Kidney Int. 2009;75(11):1166–72.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Olauson H, Lindberg K, Amin R, Jia T, Wernerson A, Andersson G, et al. Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism. J Am Soc Nephrol. 2012;23(10):1641–51.PubMedPubMedCentralGoogle Scholar
  106. 106.
    • Olauson H, Lindberg K, Amin R, Sato T, Jia T, Goetz R, et al. Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet. 2013;9(12):e1003975 Parathyroid-specific deletion of Klotho resulted in normal phosphate, calcium, and PTH levels, suggesting that FGF23 acts independent of Klotho in the parathyroid gland. PubMedPubMedCentralGoogle Scholar
  107. 107.
    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.PubMedGoogle Scholar
  108. 108.
    • Ichikawa S, Gray AK, Padgett LR, Allen MR, Clinkenbeard EL, Sarpa NM, et al. Genetic rescue of glycosylation-deficient Fgf23 in the Galnt3 knockout mouse. Endocrinology. 2014;155(10):3891–8 Generation of Galnt3 −/− /ADHR double mutants rescued the high phosphate and cFGF23 levels, demonstrating that glycosylation is required for FGF23 secretion but it does not affect its function. PubMedPubMedCentralGoogle Scholar
  109. 109.
    Francis F. 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.Google Scholar
  110. 110.
    Ruchon AF, Marcinkiewicz M, Siegfried G, Tenenhouse HS, DesGroseillers L, Crine P, et al. Pex mRNA is localized in developing mouse osteoblasts and odontoblasts. J Histochem Cytochem. 1998;46(4):459–68.PubMedGoogle Scholar
  111. 111.
    Carpinelli MR, Wicks IP, Sims NA, O'Donnell K, Hanzinikolas K, Burt R, et al. An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets. Am J Pathol. 2002;161(5):1925–33.PubMedPubMedCentralGoogle Scholar
  112. 112.
    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.PubMedGoogle Scholar
  113. 113.
    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(1):E38–49.PubMedGoogle Scholar
  114. 114.
    Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem. 2003;278(39):37419–26.PubMedGoogle Scholar
  115. 115.
    Ichikawa S, Gray AK, Bikorimana E, Econs MJ. Dosage effect of a Phex mutation in a murine model of X-linked hypophosphatemia. Calcif Tissue Int. 2013;93(2):155–62.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Yuan B, Feng JQ, Bowman S, Liu Y, Blank RD, Lindberg I, et al. Hexa-D-arginine treatment increases 7B2*PC2 activity in hyp-mouse osteoblasts and rescues the HYP phenotype. J Bone Miner Res. 2013;28(1):56–72.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Benet-Pages A, Lorenz-Depiereux B, Zischka H, White KE, Econs MJ, Strom TM. FGF23 is processed by proprotein convertases but not by PHEX. Bone. 2004;35(2):455–62.PubMedGoogle Scholar
  118. 118.
    Ichikawa S, Austin AM, Gray AK, Econs MJ. A Phex mutation in a murine model of X-linked hypophosphatemia alters phosphate responsiveness of bone cells. J Bone Miner Res. 2012;27(2):453–60.PubMedPubMedCentralGoogle Scholar
  119. 119.
    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.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Ichikawa S, Gerard-O'Riley RL, Acton D, McQueen AK, Strobel IE, Witcher PC, et al. A mutation in the Dmp1 gene alters phosphate responsiveness in mice. Endocrinology. 2017;158(3):470–6.PubMedGoogle Scholar
  121. 121.
    Lu Y, Yuan B, Qin C, Cao Z, Xie Y, Dallas SL, et al. The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa C-terminal fragment. J Bone Miner Res. 2011;26(2):331–40.PubMedGoogle Scholar
  122. 122.
    Rangiani A, Cao Z, Sun Y, Lu Y, Gao T, Yuan B, et al. Protective roles of DMP1 in high phosphate homeostasis. PLoS One. 2012;7(8):e42329.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Ababneh FK, AlSwaid A, Youssef T, Al Azzawi M, Crosby A, AlBalwi MA. Hereditary deletion of the entire FAM20C gene in a patient with Raine syndrome. Am J Med Genet A. 2013;161A(12):3155–60.PubMedGoogle Scholar
  124. 124.
    • Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, et al. Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res. 2013;28(6):1378–85 This clinical study was the first to demonstrate that FAM20c mutations are associate with FGF23-dependent hypophosphatemia. PubMedGoogle Scholar
  125. 125.
    Tagliabracci VS, Engel JL, Wen J, Wiley SE, Worby CA, Kinch LN, et al. Secreted kinase phosphorylates extracellular proteins that regulate biomineralization. Science. 2012;336(6085):1150–3.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Ishikawa HO, Xu A, Ogura E, Manning G, Irvine KD. The Raine syndrome protein FAM20C is a Golgi kinase that phosphorylates bio-mineralization proteins. PLoS One. 2012;7(8):e42988.PubMedPubMedCentralGoogle Scholar
  127. 127.
    •• Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, et al. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A. 2014;111(15):5520–5 This is the first report showing that Fam20c phosphorylates FGF23 and this prevents GALNT3-mediated O-glycosylation of FGF23, resulting in increased degradation of the intact protein. PubMedPubMedCentralGoogle Scholar
  128. 128.
    • Gattineni J, Alphonse P, Zhang Q, Mathews N, Bates CM, Baum M. Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am J Physiol Ren Physiol. 2014;306(3):F351–8 In this study, compound mutants of kidney conditional deletion of FGFR1 and global deletion of FGFR4 were generated and supporting a role for FGFR1 and FGFR4 in mediating renal FGF23-dependent phosphate metabolism. Google Scholar
  129. 129.
    • Han X, Yang J, Li L, Huang J, King G, Quarles LD. Conditional deletion of Fgfr1 in the proximal and distal tubule identifies distinct roles in phosphate and calcium transport. PLoS One. 2016;11(2):e0147845 In this study, a specific deletion of Fgfr1 in renal proximal tubules resulted in hyperphosphatemia. However, recombinant FGF23 did not reduce serum Pi levels and did not affect 1,25(OH) 2 -vitamin D 3 or PTH. PubMedPubMedCentralGoogle Scholar
  130. 130.
    Li H, Martin A, David V, Quarles LD. Compound deletion of Fgfr3 and Fgfr4 partially rescues the Hyp mouse phenotype. Am J Physiol Endocrinol Metab. 2011;300(3):E508–17.PubMedGoogle Scholar
  131. 131.
    Liu S, Vierthaler L, Tang W, Zhou J, Quarles LD. FGFR3 and FGFR4 do not mediate renal effects of FGF23. J Am Soc Nephrol. 2008;19(12):2342–50.PubMedPubMedCentralGoogle Scholar
  132. 132.
    • Xiao Z, Huang J, Cao L, Liang Y, Han X, Quarles LD. Osteocyte-specific deletion of Fgfr1 suppresses FGF23. PLoS One. 2014;9(8):e104154 In this study, osteocyte-specific deletion of FGFR1 rescued the elevated FGF23 and biochemical phenotype of the Hyp mice, suggesting this receptor plays a role in normal FGF23 production and phosphate homeostasis. PubMedPubMedCentralGoogle Scholar
  133. 133.
    Mouse Genome Sequencing C, Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, et al. Initial sequencing and comparative analysis of the mouse genome. Nature. 2002;420(6915):520–62.Google Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.INSERM U1229, RMeS, Faculté de Chirurgie Dentaire, Regenerative Medicine and SkeletonUniversité de Nantes, ONIRISNantesFrance
  2. 2.Department of Basic Science and Craniofacial BiologyNew York University College of DentistryNew YorkUSA
  3. 3.Department of MedicineNew York University School of MedicineNew YorkUSA

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