Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters

  • Ming Chang HuEmail author
  • Mingjun Shi
  • Orson W. MoeEmail author
Invited Review


Alpha-Klotho is a member of the Klotho family consisting of two other single-pass transmembrane proteins: βKlotho and γKlotho; αKlotho has been shown to circulate in the blood. Fibroblast growth factor (FGF)23 is a member of the FGF superfamily of 22 genes/proteins. αKlotho serves as a co-receptor with FGF receptors (FGFRs) to provide a receptacle for physiological FGF23 signaling including regulation of phosphate metabolism. The extracellular domain of transmembrane αKlotho is shed by secretases and released into blood circulation (soluble αKlotho). Soluble αKlotho has both FGF23-independent and FGF23-dependent roles in phosphate homeostasis by modulating intestinal phosphate absorption, urinary phosphate excretion, and phosphate distribution into bone in concerted interaction with other calciophosphotropic hormones such as PTH and 1,25-(OH)2D. The direct role of αKlotho and FGF23 in the maintenance of phosphate homeostasis is partly mediated by modulation of type II Na+-dependent phosphate co-transporters in target organs. αKlotho and FGF23 are principal phosphotropic hormones, and the manipulation of the αKlotho-FGF23 axis is a novel therapeutic strategy for genetic and acquired phosphate disorders and for conditions with FGF23 excess and αKlotho deficiency such as chronic kidney disease.


αKlotho FGF23 FGF receptor Phosphate homeostasis Na-dependent phosphate co-transporter 


Funding information

The authors acknowledge the grant support from the National Institutes of Health (NIDDK-R01-DK091392, NIDDK-R01-DK092461, NIDDK-R01-DK092461-6A1) and the George O’Brien Kidney Research Center at the University of Texas Southwestern Medical Center (NIDDK-P30-DK079328), the Charles and Jane Pak Center Innovative Research Support and Endowed Professor Collaborative Research Support, the Pak-Seldin Center for Metabolic and Clinical Research, and the Simmons Family Foundation.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Akasaka-Manya K, Manya H, Kizuka Y, Oka S, Endo T (2014) alpha-Klotho mice demonstrate increased expression of the non-sulfated N-glycan form of the HNK-1 glyco-epitope in kidney tissue. J Biochem 156:107–113. PubMedCrossRefGoogle Scholar
  2. 2.
    Andrukhova O, Zeitz U, Goetz R, Mohammadi M, Lanske B, Erben RG (2012) FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway. Bone 51:621–628. PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Baum M, Moe OW, Zhang J, Dwarakanath V, Quigley R (2005) Phosphatonin washout in Hyp mice proximal tubules: evidence for posttranscriptional regulation. Am J Physiol Renal Physiol 288:F363–F370. PubMedCrossRefGoogle Scholar
  4. 4.
    Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117:4003–4008. PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B (2005) An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 14:385–390. PubMedCrossRefGoogle Scholar
  6. 6.
    Biber J, Custer M, Magagnin S, Hayes G, Werner A, Lotscher M, Kaissling B, Murer H (1996) Renal Na/Pi-cotransporters. Kidney Int 49:981–985PubMedCrossRefGoogle Scholar
  7. 7.
    Biber J, Hernando N, Forster I (2013) Phosphate transporters and their function. Annu Rev Physiol 75:535–550. PubMedCrossRefGoogle Scholar
  8. 8.
    Bloch L, Sineshchekova O, Reichenbach D, Reiss K, Saftig P, Kuro-o M, Kaether C (2009) Klotho is a substrate for alpha-, beta- and gamma-secretase. FEBS Lett 583:3221–3224. PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Bon N, Frangi G, Sourice S, Guicheux J, Beck-Cormier S, Beck L (2018) Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2. Mol Metab.
  10. 10.
    Bonewald LF, Wacker MJ (2013) FGF23 production by osteocytes. Pediatr Nephrol 28:563–568. PubMedCrossRefGoogle Scholar
  11. 11.
    Burnett-Bowie SM, Henao MP, Dere ME, Lee H, Leder BZ (2009) Effects of hPTH(1-34) infusion on circulating serum phosphate, 1,25-dihydroxyvitamin D, and FGF23 levels in healthy men. J Bone Miner Res 24:1681–1685. PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Capuano P, Bacic D, Stange G, Hernando N, Kaissling B, Pal R, Kocher O, Biber J, Wagner CA, Murer H (2005) Expression and regulation of the renal Na/phosphate cotransporter NaPi-IIa in a mouse model deficient for the PDZ protein PDZK1. Pflugers Arch 449:392–402. PubMedCrossRefGoogle Scholar
  13. 13.
    Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro OM, Huang CL (2008) Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci U S A 105:9805–9810. PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Cha SK, Hu MC, Kurosu H, Kuro-o M, Moe O, Huang CL (2009) Regulation of renal outer medullary potassium channel and renal K(+) excretion by Klotho. Mol Pharmacol 76:38–46. PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR (2007) Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A 104:19796–19801. PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Chen G, Liu Y, Goetz R, Fu L, Jayaraman S, Hu MC, Moe OW, Liang G, Li X, Mohammadi M (2018) alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 553:461–466. PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Clinkenbeard EL, Cass TA, Ni P, Hum JM, Bellido T, Allen MR, White KE (2016) Conditional deletion of murine Fgf23: interruption of the normal skeletal responses to phosphate challenge and rescue of genetic hypophosphatemia. J Bone Miner Res 31:1247–1257. PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Clinkenbeard EL, White KE (2016) Systemic control of bone homeostasis by FGF23 signaling. Curr Mol Biol Rep 2:62–71. PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Consortium A (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26:345–348. CrossRefGoogle Scholar
  20. 20.
    Dermaku-Sopjani M, Sopjani M, Saxena A, Shojaiefard M, Bogatikov E, Alesutan I, Eichenmuller M, Lang F (2011) Downregulation of NaPi-IIa and NaPi-IIb Na-coupled phosphate transporters by coexpression of Klotho. Cell Physiol Biochem 28:251–258. PubMedCrossRefGoogle Scholar
  21. 21.
    Eren M, Place AT, Thomas PM, Flevaris P, Miyata T, Vaughan DE (2017) PAI-1 is a critical regulator of FGF23 homeostasis. Sci Adv 3:e1603259. PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Feng JQ, Ye L, Schiavi S (2009) Do osteocytes contribute to phosphate homeostasis? Curr Opin Nephrol Hypertens 18:285–291. PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Feng JQ, Clinkenbeard EL, Yuan B, White KE, Drezner MK (2013) Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone 54:213–221. PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Foley RN (2009) Phosphate levels and cardiovascular disease in the general population. Clin J Am Soc Nephrol 4:1136–1139. PubMedCrossRefGoogle Scholar
  25. 25.
    Forster IC, Hernando N, Biber J, Murer H (2006) Proximal tubular handling of phosphate: a molecular perspective. Kidney Int 70:1548–1559. PubMedCrossRefGoogle Scholar
  26. 26.
    Forster IC, Hernando N, Biber J, Murer H (2012) Phosphate transport kinetics and structure-function relationships of SLC34 and SLC20 proteins. Curr Top Membr 70:313–356. PubMedCrossRefGoogle Scholar
  27. 27.
    Forster IC, Hernando N, Biber J, Murer H (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol Asp Med 34:386–395. CrossRefGoogle Scholar
  28. 28.
    Fukumoto S (2014) Phosphate metabolism and vitamin D. Bonekey Rep 3(497).
  29. 29.
    Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, Jafar TH, Heerspink HJ, Mann JF, Matsushita K, Wen CP (2013) Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 382:339–352. PubMedCrossRefGoogle Scholar
  30. 30.
    Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M (2009) FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 297:F282–F291. PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gattineni J, Twombley K, Goetz R, Mohammadi M, Baum M (2011) Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4. Am J Physiol Renal Physiol 301:F371–F377. PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Gattineni J, Baum M (2012) Genetic disorders of phosphate regulation. Pediatr Nephrol 27:1477–1487. PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gattineni J, Alphonse P, Zhang Q, Mathews N, Bates CM, Baum M (2014) Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am J Physiol Renal Physiol 306:F351–F358. PubMedCrossRefGoogle Scholar
  34. 34.
    Goetz R, Nakada Y, Hu MC, Kurosu H, Wang L, Nakatani T, Shi M, Eliseenkova AV, Razzaque MS, Moe OW, Kuro-o M, Mohammadi M (2010) Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci U S A 107:407–412. PubMedCrossRefGoogle Scholar
  35. 35.
    Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, Li J, Shehadeh LA, Hare JM, David V, Martin A, Fornoni A, Di Marco GS, Kentrup D, Reuter S, Mayer AB, Pavenstadt H, Stypmann J, Kuhn C, Hille S, Frey N, Leifheit-Nestler M, Richter B, Haffner D, Abraham R, Bange J, Sperl B, Ullrich A, Brand M, Wolf M, Faul C (2015) Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab 22:1020–1032. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Guo YC, Yuan Q (2015) Fibroblast growth factor 23 and bone mineralisation. Int J Oral Sci 7:8–13. PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Hernando N, Myakala K, Simona F, Knopfel T, Thomas L, Murer H, Wagner CA, Biber J (2015) Intestinal depletion of NaPi-IIb/Slc34a2 in mice: renal and hormonal adaptation. J Bone Miner Res 30:1925–1937. PubMedCrossRefGoogle Scholar
  38. 38.
    Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, Razzaque MS, Rosenblatt KP, Baum MG, Kuro-o M, Moe OW (2010) Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 24:3438–3450. PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Hu MC, Shi M, Zhang J, Quinones H, Griffith C, Kuro-o M, Moe OW (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22:124–136. PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Hu MC, Shiizaki K, Kuro-o M, Moe OW (2013) Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 75:503–533. PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Hu MC, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, Shelton J, Amaral AP, Faul C, Taniguchi M, Wolf M, Brand M, Takahashi M, Kuro OM, Hill JA, Moe OW (2015) Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 26:1290–1302. PubMedCrossRefGoogle Scholar
  42. 42.
    Hu MC, Shi M, Zhang J, Addo T, Cho HJ, Barker SL, Ravikumar P, Gillings N, Bian A, Sidhu SS, Kuro-o M, Moe OW (2016) Renal production, uptake, and handling of circulating alphaKlotho. J Am Soc Nephrol 27:79–90. PubMedCrossRefGoogle Scholar
  43. 43.
    Ichikawa S, Sorenson AH, Austin AM, Mackenzie DS, Fritz TA, Moh A, Hui SL, Econs MJ (2009) Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression. Endocrinology 150:2543–2550. PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y (2004) Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 565:143–147. PubMedCrossRefGoogle Scholar
  45. 45.
    John GB, Cheng CY, Kuro-o M (2011) Role of Klotho in aging, phosphate metabolism, and CKD. Am J Kidney Dis 58:127–134. PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Kaludjerovic J, Komaba H, Sato T, Erben RG, Baron R, Olauson H, Larsson TE, Lanske B (2017) Klotho expression in long bones regulates FGF23 production during renal failure. FASEB J 31:2050–2064. PubMedCrossRefGoogle Scholar
  47. 47.
    Kawaguchi H, Manabe N, Miyaura C, Chikuda H, Nakamura K, Kuro-o M (1999) Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. J Clin Invest 104:229–237. PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kawaguchi H, Manabe N, Chikuda H, Nakamura K, Kuroo M (2000) Cellular and molecular mechanism of low-turnover osteopenia in the klotho-deficient mouse. Cell Mol Life Sci 57:731–737PubMedCrossRefGoogle Scholar
  49. 49.
    Kemper MJ, van Husen M (2014) Renal osteodystrophy in children: pathogenesis, diagnosis and treatment. Curr Opin Pediatr 26:180–186. PubMedCrossRefGoogle Scholar
  50. 50.
    Komaba H, Kaludjerovic J, Hu DZ, Nagano K, Amano K, Ide N, Sato T, Densmore MJ, Hanai JI, Olauson H, Bellido T, Larsson TE, Baron R, Lanske B (2017) Klotho expression in osteocytes regulates bone metabolism and controls bone formation. Kidney Int 92:599–611. PubMedCrossRefGoogle Scholar
  51. 51.
    Kumar R, Thompson JR (2011) The regulation of parathyroid hormone secretion and synthesis. J Am Soc Nephrol 22:216–224. PubMedCrossRefGoogle Scholar
  52. 52.
    Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51. PubMedCrossRefGoogle Scholar
  53. 53.
    Kuro-o M (2006) Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens 15:437–441. PubMedCrossRefGoogle Scholar
  54. 54.
    Lau WL, Leaf EM, Hu MC, Takeno MM, Kuro-o M, Moe OW, Giachelli CM (2012) Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int 82:1261–1270. PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Lederer E (2014) Regulation of serum phosphate. J Physiol 592:3985–3995. PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Lee S, Choi J, Mohanty J, Sousa LP, Tome F, Pardon E, Steyaert J, Lemmon MA, Lax I, Schlessinger J (2018) Structures of beta-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling. Nature 553:501–505. PubMedCrossRefGoogle Scholar
  57. 57.
    Leunissen EH, Nair AV, Bull C, Lefeber DJ, van Delft FL, Bindels RJ, Hoenderop JG (2013) The epithelial calcium channel TRPV5 is regulated differentially by klotho and sialidase. J Biol Chem 288:29238–29246. PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Liu S, Gupta A, Quarles LD (2007) Emerging role of fibroblast growth factor 23 in a bone-kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization. Curr Opin Nephrol Hypertens 16:329–335. PubMedCrossRefGoogle Scholar
  59. 59.
    Lundquist P, Murer H, Biber J (2007) Type II Na+-Pi cotransporters in osteoblast mineral formation: regulation by inorganic phosphate. Cell Physiol Biochem 19:43–56. PubMedCrossRefGoogle Scholar
  60. 60.
    Madjdpour C, Bacic D, Kaissling B, Murer H, Biber J (2004) Segment-specific expression of sodium-phosphate cotransporters NaPi-IIa and -IIc and interacting proteins in mouse renal proximal tubules. Pflugers Arch 448:402–410. PubMedCrossRefGoogle Scholar
  61. 61.
    Magagnin S, Werner A, Markovich D, Sorribas V, Stange G, Biber J, Murer H (1993) Expression cloning of human and rat renal cortex Na/Pi cotransport. Proc Natl Acad Sci U S A 90:5979–5983PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Marks J, Debnam ES, Unwin RJ (2010) Phosphate homeostasis and the renal-gastrointestinal axis. Am J Physiol Renal Physiol 299:F285–F296. PubMedCrossRefGoogle Scholar
  63. 63.
    Miyamoto K, Segawa H, Ito M, Kuwahata M (2004) Physiological regulation of renal sodium-dependent phosphate cotransporters. Jpn J Physiol 54:93–102PubMedCrossRefGoogle Scholar
  64. 64.
    Miyamoto K, Ito M, Kuwahata M, Kato S, Segawa H (2005) Inhibition of intestinal sodium-dependent inorganic phosphate transport by fibroblast growth factor 23. Ther Apher Dial 9:331–335. PubMedCrossRefGoogle Scholar
  65. 65.
    Moe OW (2009) PiT-2 coming out of the pits. Am J Physiol Renal Physiol 296:F689–F690. PubMedCrossRefGoogle Scholar
  66. 66.
    Nakatani T, Ohnishi M, Razzaque MS (2009) Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model. FASEB J 23:3702–3711. PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Nakatani T, Sarraj B, Ohnishi M, Densmore MJ, Taguchi T, Goetz R, Mohammadi M, Lanske B, Razzaque MS (2009) In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23)-mediated regulation of systemic phosphate homeostasis. FASEB J 23:433–441. PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Neyra JA, Moe OW, Hu MC (2015) Fibroblast growth factor 23 and acute kidney injury. Pediatr Nephrol 30:1909–1918. PubMedCrossRefGoogle Scholar
  69. 69.
    Oikonomou KA, Orfanidou TI, Vlychou MK, Kapsoritakis AN, Tsezou A, Malizos KN, Potamianos SP (2014) Lower fibroblast growth factor 23 levels in young adults with Crohn disease as a possible secondary compensatory effect on the disturbance of bone and mineral metabolism. J Clin Densitom 17:177–184. PubMedCrossRefGoogle Scholar
  70. 70.
    Prie D, Friedlander G (2010) Reciprocal control of 1,25-dihydroxyvitamin D and FGF23 formation involving the FGF23/Klotho system. Clin J Am Soc Nephrol 5:1717–1722. PubMedCrossRefGoogle Scholar
  71. 71.
    Quarles LD (2012) Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res 318:1040–1048. PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Quarles LD (2012) Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nat Rev Endocrinol 8:276–286. PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Radanovic T, Murer H, Biber J (2003) Expression of the Na/P(i)-cotransporter type IIb in Sf9 cells: functional characterization and purification. J Membr Biol 194:91–96. PubMedCrossRefGoogle Scholar
  74. 74.
    Radanovic T, Wagner CA, Murer H, Biber J (2005) Regulation of intestinal phosphate transport. I. Segmental expression and adaptation to low-P(i) diet of the type IIb Na(+)-P(i) cotransporter in mouse small intestine. Am J Physiol Gastrointest Liver Physiol 288:G496–G500. PubMedCrossRefGoogle Scholar
  75. 75.
    Razzaque MS, Lanske B (2006) Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice. Trends Mol Med 12:298–305. PubMedCrossRefGoogle Scholar
  76. 76.
    Razzaque MS (2012) FGF23, klotho and vitamin D interactions: what have we learned from in vivo mouse genetics studies? Adv Exp Med Biol 728:84–91. PubMedCrossRefGoogle Scholar
  77. 77.
    Richter B, Faul C (2018) FGF23 actions on target tissues-with and without Klotho. Front Endocrinol (Lausanne) 9(189).
  78. 78.
    Sabbagh Y, O’Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, Schiavi SC (2009) Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol 20:2348–2358. PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Sabbagh Y, Giral H, Caldas Y, Levi M, Schiavi SC (2011) Intestinal phosphate transport. Adv Chronic Kidney Dis 18:85–90. PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Saito T, Fukumoto S (2009) Fibroblast growth factor 23 (FGF23) and disorders of phosphate metabolism. Int J Pediatr Endocrinol 2009(496514):1–6. CrossRefGoogle Scholar
  81. 81.
    Saji F, Shigematsu T, Sakaguchi T, Ohya M, Orita H, Maeda Y, Ooura M, Mima T, Negi S (2010) Fibroblast growth factor 23 production in bone is directly regulated by 1{alpha},25-dihydroxyvitamin D, but not PTH. Am J Physiol Renal Physiol 299:F1212–F1217. PubMedCrossRefGoogle Scholar
  82. 82.
    Sapir-Koren R, Livshits G (2014) Bone mineralization is regulated by signaling cross talk between molecular factors of local and systemic origin: the role of fibroblast growth factor 23. Biofactors 40:555–568. PubMedCrossRefGoogle Scholar
  83. 83.
    Segawa H, Yamanaka S, Ohno Y, Onitsuka A, Shiozawa K, Aranami F, Furutani J, Tomoe Y, Ito M, Kuwahata M, Imura A, Nabeshima Y, Miyamoto K (2007) Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice. Am J Physiol Renal Physiol 292:F769–F779. PubMedCrossRefGoogle Scholar
  84. 84.
    Shalhoub V, Ward SC, Sun B, Stevens J, Renshaw L, Hawkins N, Richards WG (2011) Fibroblast growth factor 23 (FGF23) and alpha-klotho stimulate osteoblastic MC3T3.E1 cell proliferation and inhibit mineralization. Calcif Tissue Int 89:140–150. PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113:561–568. PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Shimada T, Yamazaki Y, Takahashi M, Hasegawa H, Urakawa I, Oshima T, Ono K, Kakitani M, Tomizuka K, Fujita T, Fukumoto S, Yamashita T (2005) Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol 289:F1088–F1095. PubMedCrossRefGoogle Scholar
  87. 87.
    Sidney S, Quesenberry CP Jr, Jaffe MG, Sorel M, Nguyen-Huynh MN, Kushi LH, Go AS, Rana JS (2016) Recent trends in cardiovascular mortality in the United States and public health goals. JAMA Cardiol 1:594–599. PubMedCrossRefGoogle Scholar
  88. 88.
    Stauber A, Radanovic T, Stange G, Murer H, Wagner CA, Biber J (2005) Regulation of intestinal phosphate transport. II. Metabolic acidosis stimulates Na(+)-dependent phosphate absorption and expression of the Na(+)-P(i) cotransporter NaPi-IIb in small intestine. Am J Physiol Gastrointest Liver Physiol 288:G501–G506. PubMedCrossRefGoogle Scholar
  89. 89.
    Stubbs J, Liu S, Quarles LD (2007) Role of fibroblast growth factor 23 in phosphate homeostasis and pathogenesis of disordered mineral metabolism in chronic kidney disease. Semin Dial 20:302–308. PubMedCrossRefGoogle Scholar
  90. 90.
    Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, Koller A, Nizet V, White KE, Dixon JE (2014) Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A 111:5520–5525. PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Takenaka T, Watanabe Y, Inoue T, Miyazaki T, Suzuki H (2013) Fibroblast growth factor 23 enhances renal klotho abundance. Pflugers Arch 465:935–943. PubMedCrossRefGoogle Scholar
  92. 92.
    Tohyama O, Imura A, Iwano A, Freund JN, Henrissat B, Fujimori T, Nabeshima Y (2004) Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem 279:9777–9784. PubMedCrossRefGoogle Scholar
  93. 93.
    Tomoe Y, Segawa H, Shiozawa K, Kaneko I, Tominaga R, Hanabusa E, Aranami F, Furutani J, Kuwahara S, Tatsumi S, Matsumoto M, Ito M, Miyamoto K (2010) Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice. Am J Physiol Renal Physiol 298:F1341–F1350. PubMedCrossRefGoogle Scholar
  94. 94.
    Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y (2003) Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 17:2393–2403. PubMedCrossRefGoogle Scholar
  95. 95.
    Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770–774. PubMedCrossRefGoogle Scholar
  96. 96.
    van Husen M, Fischer AK, Lehnhardt A, Klaassen I, Moller K, Muller-Wiefel DE, Kemper MJ (2010) Fibroblast growth factor 23 and bone metabolism in children with chronic kidney disease. Kidney Int 78:200–206. PubMedCrossRefGoogle Scholar
  97. 97.
    van Loon EP, Pulskens WP, van der Hagen EA, Lavrijsen M, Vervloet MG, van Goor H, Bindels RJ, Hoenderop JG (2015) Shedding of klotho by ADAMs in the kidney. Am J Physiol Renal Physiol 309:F359–F368. PubMedCrossRefGoogle Scholar
  98. 98.
    Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, Biber J, Forster IC (2009) The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. Am J Physiol Renal Physiol 296:F691–F699. PubMedCrossRefGoogle Scholar
  99. 99.
    Voelkl J, Alesutan I, Leibrock CB, Quintanilla-Martinez L, Kuhn V, Feger M, Mia S, Ahmed MS, Rosenblatt KP, Kuro OM, Lang F (2013) Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice. J Clin Invest 123:812–822. PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Wagner CA, Hernando N, Forster IC, Biber J (2014) The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch 466:139–153. PubMedCrossRefGoogle Scholar
  101. 101.
    Werner A, Dehmelt L, Nalbant P (1998) Na+-dependent phosphate cotransporters: the NaPi protein families. J Exp Biol 201:3135–3142PubMedGoogle Scholar
  102. 102.
    White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ (2001) Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 60:2079–2086. PubMedCrossRefGoogle Scholar
  103. 103.
    Wolf MT, An SW, Nie M, Bal MS, Huang CL (2014) Klotho up-regulates renal calcium channel transient receptor potential vanilloid 5 (TRPV5) by intra- and extracellular N-glycosylation-dependent mechanisms. J Biol Chem 289:35849–35857. PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Xia WB, Jiang Y, Li M, Xing XP, Wang O, Hu YY, Zhang HB, Liu HC, Meng XW, Zhou XY (2010) Levels and dynamic changes of serum fibroblast growth factor 23 in hypophosphatemic rickets/osteomalacia. Chin Med J 123:1158–1162PubMedGoogle Scholar
  105. 105.
    Xu L, Zhang L, Zhang H, Yang Z, Qi L, Wang Y, Ren S (2018) The participation of fibroblast growth factor 23 (FGF23) in the progression of osteoporosis via JAK/STAT pathway. J Cell Biochem 119:3819–3828. PubMedCrossRefGoogle Scholar
  106. 106.
    Yamashita T, Nifuji A, Furuya K, Nabeshima Y, Noda M (1998) Elongation of the epiphyseal trabecular bone in transgenic mice carrying a klotho gene locus mutation that leads to a syndrome resembling aging. J Endocrinol 159:1–8PubMedCrossRefGoogle Scholar
  107. 107.
    Yamashita T, Nabeshima Y, Noda M (2000) High-resolution micro-computed tomography analyses of the abnormal trabecular bone structures in klotho gene mutant mice. J Endocrinol 164:239–245PubMedCrossRefGoogle Scholar
  108. 108.
    Yamashita T, Yoshitake H, Tsuji K, Kawaguchi N, Nabeshima Y, Noda M (2000) Retardation in bone resorption after bone marrow ablation in klotho mutant mice. Endocrinology 141:438–445. PubMedCrossRefGoogle Scholar
  109. 109.
    Yoshida T, Fujimori T, Nabeshima Y (2002) Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene. Endocrinology 143:683–689. PubMedCrossRefGoogle Scholar
  110. 110.
    Zhang W, Xue D, Hu D, Xie T, Tao Y, Zhu T, Chen E, Pan Z (2015) Secreted klotho protein attenuates osteogenic differentiation of human bone marrow mesenchymal stem cells in vitro via inactivation of the FGFR1/ERK signaling pathway. Growth Factors 33:356–365. PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Charles and Jane Pak Center for Mineral Metabolism and Clinical ResearchUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasUSA
  3. 3.Department of PhysiologyUniversity of Texas Southwestern Medical CenterDallasUSA

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