Advertisement

pp 1-28 | Cite as

FGF23 and Bone and Mineral Metabolism

  • Seiji Fukumoto
Chapter
Part of the Handbook of Experimental Pharmacology book series

Abstract

FGF23 is a phosphotropic hormone produced by the bone. FGF23 works by binding to the FGF receptor-Klotho complex. Klotho is expressed in several limited tissues including the kidney and parathyroid glands. This tissue-restricted expression of Klotho is believed to determine the target organs of FGF23. FGF23 reduces serum phosphate by suppressing the expression of type 2a and 2c sodium-phosphate cotransporters in renal proximal tubules. FGF23 also decreases 1,25-dihydroxyvitamin D levels by regulating the expression of vitamin D-metabolizing enzymes, which results in reduced intestinal phosphate absorption. Excessive actions of FGF23 cause several types of hypophosphatemic rickets/osteomalacia characterized by impaired mineralization of bone matrix. In contrast, deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis with high 1,25-dihydroxyvitamin D levels. These results indicate that FGF23 is a physiological regulator of phosphate and vitamin D metabolism and indispensable for the maintenance of serum phosphate levels.

Keywords

Hyperphosphatemia Hypophosphatemia Klotho Osteomalacia Rickets Tumoral calcinosis 

References

  1. 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(3):621–628.  https://doi.org/10.1016/j.bone.2012.05.015CrossRefGoogle Scholar
  2. Andrukhova O, Slavic S, Smorodchenko A, Zeitz U, Shalhoub V, Lanske B, Pohl EE, Erben RG (2014a) FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med 6(6):744–759.  https://doi.org/10.1002/emmm.201303716CrossRefGoogle Scholar
  3. Andrukhova O, Smorodchenko A, Egerbacher M, Streicher C, Zeitz U, Goetz R, Shalhoub V, Mohammadi M, Pohl EE, Lanske B, Erben RG (2014b) FGF23 promotes renal calcium reabsorption through the TRPV5 channel. EMBO J 33(3):229–246.  https://doi.org/10.1002/embj.201284188CrossRefGoogle Scholar
  4. Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, Fujita T, Wada M, Yamashita T, Fukumoto S, Shimada T (2009) Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res 24(11):1879–1888.  https://doi.org/10.1359/jbmr.090509CrossRefGoogle Scholar
  5. Aono Y, Hasegawa H, Yamazaki Y, Shimada T, Fujita T, Yamashita T, Fukumoto S (2011) Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. J Bone Miner Res 26(4):803–810.  https://doi.org/10.1002/jbmr.275CrossRefGoogle Scholar
  6. Araya K, Fukumoto S, Backenroth R, Takeuchi Y, Nakayama K, Ito N, Yoshii N, Yamazaki Y, Yamashita T, Silver J, Igarashi T, Fujita T (2005) A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab 90(10):5523–5527.  https://doi.org/10.1210/jc.2005-0301CrossRefGoogle Scholar
  7. Avitan-Hersh E, Tatur S, Indelman M, Gepstein V, Shreter R, Hershkovitz D, Brick R, Bergman R, Tiosano D (2014) Postzygotic HRAS mutation causing both keratinocytic epidermal nevus and thymoma and associated with bone dysplasia and hypophosphatemia due to elevated FGF23. J Clin Endocrinol Metab 99(1):E132–E136.  https://doi.org/10.1210/jc.2013-2813CrossRefGoogle Scholar
  8. Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, Tenenhouse HS (1997) 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 99(6):1200–1209.  https://doi.org/10.1172/jci119276CrossRefGoogle Scholar
  9. 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(12):4003–4008.  https://doi.org/10.1172/jci32409CrossRefGoogle Scholar
  10. 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(3):385–390.  https://doi.org/10.1093/hmg/ddi034CrossRefGoogle Scholar
  11. Bennett EP, Mandel U, Clausen H, Gerken TA, Fritz TA, Tabak LA (2012) Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family. Glycobiology 22(6):736–756.  https://doi.org/10.1093/glycob/cwr182CrossRefGoogle Scholar
  12. Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan K, Tenenhouse HS, Juppner H (2006) 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 78(2):179–192.  https://doi.org/10.1086/499409CrossRefGoogle Scholar
  13. Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R, Jan De Beur SM, Schiavi SC, Kumar R (2003) Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest 112(5):785–794.  https://doi.org/10.1172/jci18563CrossRefGoogle Scholar
  14. Breer S, Brunkhorst T, Beil FT, Peldschus K, Heiland M, Klutmann S, Barvencik F, Zustin J, Gratz KF, Amling M (2014) 68Ga DOTA-TATE PET/CT allows tumor localization in patients with tumor-induced osteomalacia but negative 111In-octreotide SPECT/CT. Bone 64:222–227.  https://doi.org/10.1016/j.bone.2014.04.016CrossRefGoogle Scholar
  15. Brown WW, Juppner H, Langman CB, Price H, Farrow EG, White KE, McCormick KL (2009) Hypophosphatemia with elevations in serum fibroblast growth factor 23 in a child with Jansen's metaphyseal chondrodysplasia. J Clin Endocrinol Metab 94(1):17–20.  https://doi.org/10.1210/jc.2008-022010.1210/jcem.94.2.9988CrossRefGoogle Scholar
  16. Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, Nabeshima Y, Reyes-Mugica M, Carpenter TO, Lifton RP (2008) A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U S A 105(9):3455–3460.  https://doi.org/10.1073/pnas.0712361105CrossRefGoogle Scholar
  17. Carpenter TO, Ellis BK, Insogna KL, Philbrick WM, Sterpka J, Shimkets R (2005) Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J Clin Endocrinol Metab 90(2):1012–1020.  https://doi.org/10.1210/jc.2004-0357CrossRefGoogle Scholar
  18. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL (2011) A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res 26(7):1381–1388.  https://doi.org/10.1002/jbmr.340CrossRefGoogle Scholar
  19. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, Kawakami T, Ito T, Zhang X, Humphrey J, Insogna KL, Peacock M (2014) Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest 124(4):1587–1597.  https://doi.org/10.1172/jci72829CrossRefGoogle Scholar
  20. Carpenter TO, Whyte MP, Imel EA, Boot AM, Hogler W, Linglart A, Padidela R, Van’t Hoff W, Mao M, Chen CY, Skrinar A, Kakkis E, San Martin J, Portale AA (2018) Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med 378(21):1987–1998.  https://doi.org/10.1056/NEJMoa1714641CrossRefGoogle Scholar
  21. 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(7689):461–466.  https://doi.org/10.1038/nature25451CrossRefGoogle Scholar
  22. The HYP Consortium (1995) A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 11(2):130–136.  https://doi.org/10.1038/ng1095-130Google Scholar
  23. ADHR Consortium (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26(3):345–348.  https://doi.org/10.1038/81664Google Scholar
  24. David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89(1):135–146.  https://doi.org/10.1038/ki.2015.290CrossRefGoogle Scholar
  25. Dehghani A, Hafizibarjin Z, Najjari R, Kaseb F, Safari F (2018) Resveratrol and 1,25-dihydroxyvitamin D co-administration protects the heart against D-galactose-induced aging in rats: evaluation of serum and cardiac levels of klotho. Aging Clin Exp Res.  https://doi.org/10.1007/s40520-018-1075-xGoogle Scholar
  26. Endo I, Fukumoto S, Ozono K, Namba N, Tanaka H, Inoue D, Minagawa M, Sugimoto T, Yamauchi M, Michigami T, Matsumoto T (2008) Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: proposal of diagnostic criteria using FGF23 measurement. Bone 42(6):1235–1239.  https://doi.org/10.1016/j.bone.2008.02.014CrossRefGoogle Scholar
  27. Farrow EG, Yu X, Summers LJ, Davis SI, Fleet JC, Allen MR, Robling AG, Stayrook KR, Jideonwo V, Magers MJ, Garringer HJ, Vidal R, Chan RJ, Goodwin CB, Hui SL, Peacock M, White KE (2011) Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A 108(46):E1146–E1155.  https://doi.org/10.1073/pnas.1110905108CrossRefGoogle Scholar
  28. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, Rios H, Drezner MK, Quarles LD, Bonewald LF, White KE (2006) Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 38(11):1310–1315.  https://doi.org/10.1038/ng1905CrossRefGoogle Scholar
  29. Ferrari SL, Bonjour JP, Rizzoli R (2005) Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab 90(3):1519–1524.  https://doi.org/10.1210/jc.2004-1039CrossRefGoogle Scholar
  30. Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, Econs MJ, Inwards CY, Jan de Beur SM, Mentzel T, Montgomery E, Michal M, Miettinen M, Mills SE, Reith JD, O’Connell JX, Rosenberg AE, Rubin BP, Sweet DE, Vinh TN, Wold LE, Wehrli BM, White KE, Zaino RJ, Weiss SW (2004) Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol 28(1):1–30Google Scholar
  31. Frishberg Y, Ito N, Rinat C, Yamazaki Y, Feinstein S, Urakawa I, Navon-Elkan P, Becker-Cohen R, Yamashita T, Araya K, Igarashi T, Fujita T, Fukumoto S (2007) Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J Bone Miner Res 22(2):235–242.  https://doi.org/10.1359/jbmr.061105CrossRefGoogle Scholar
  32. Fukumoto S (2018) Targeting fibroblast growth factor 23 signaling with antibodies and inhibitors, is there a rationale? Front Endocrinol 9:48.  https://doi.org/10.3389/fendo.2018.00048CrossRefGoogle Scholar
  33. Fukumoto S, Shimizu Y (2011) Fibroblast growth factor 23 as a phosphotropic hormone and beyond. J Bone Miner Metab 29(5):507–514.  https://doi.org/10.1007/s00774-011-0298-0CrossRefGoogle Scholar
  34. 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(2):F282–F291.  https://doi.org/10.1152/ajprenal.90742.2008CrossRefGoogle Scholar
  35. 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(2):F371–F377.  https://doi.org/10.1152/ajprenal.00740.2010CrossRefGoogle Scholar
  36. Goetz R, Mohammadi M (2013) Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol 14(3):166–180.  https://doi.org/10.1038/nrm3528CrossRefGoogle Scholar
  37. 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(1):407–412.  https://doi.org/10.1073/pnas.0902006107CrossRefGoogle Scholar
  38. 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(6):1020–1032.  https://doi.org/10.1016/j.cmet.2015.09.002CrossRefGoogle Scholar
  39. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Juppner H, Wolf M (2008) Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359(6):584–592.  https://doi.org/10.1056/NEJMoa0706130CrossRefGoogle Scholar
  40. Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A (2019) Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 15(7):435–455.  https://doi.org/10.1038/s41581-019-0152-5CrossRefGoogle Scholar
  41. Han X, Li L, Yang J, King G, Xiao Z, Quarles LD (2016) Counter-regulatory paracrine actions of FGF-23 and 1,25(OH)2 D in macrophages. FEBS Lett 590(1):53–67.  https://doi.org/10.1002/1873-3468.12040CrossRefGoogle Scholar
  42. Hasegawa H, Nagano N, Urakawa I, Yamazaki Y, Iijima K, Fujita T, Yamashita T, Fukumoto S, Shimada T (2010) Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. Kidney Int 78(10):975–980.  https://doi.org/10.1038/ki.2010.313CrossRefGoogle Scholar
  43. Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, O’Malley BW (1988) Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 242(4886):1702–1705.  https://doi.org/10.1126/science.2849209CrossRefGoogle Scholar
  44. Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, Goetz R, Mohammadi M, White KE, Econs MJ (2007) A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117(9):2684–2691.  https://doi.org/10.1172/jci31330CrossRefGoogle Scholar
  45. Imel EA, Hui SL, Econs MJ (2007) FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res 22(4):520–526.  https://doi.org/10.1359/jbmr.070107CrossRefGoogle Scholar
  46. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Hogler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA (2019) Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet 393(10189):2416–2427.  https://doi.org/10.1016/s0140-6736(19)30654-3CrossRefGoogle Scholar
  47. Insogna KL, Briot K, Imel EA, Kamenicky P, Ruppe MD, Portale AA, Weber T, Pitukcheewanont P, Cheong HI, Jan de Beur S, Imanishi Y, Ito N, Lachmann RH, Tanaka H, Perwad F, Zhang L, Chen CY, Theodore-Oklota C, Mealiffe M, San Martin J, Carpenter TO (2018) A randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of Burosumab, an anti-FGF23 antibody, in adults with X-linked hypophosphatemia: week 24 primary analysis. J Bone Miner Res 33(8):1383–1393.  https://doi.org/10.1002/jbmr.3475CrossRefGoogle Scholar
  48. Insogna KL, Rauch F, Kamenicky P, Ito N, Kubota T, Nakamura A, Zhang L, Mealiffe M, San Martin J, Portale AA (2019) Burosumab improved histomorphometric measures of osteomalacia in adults with X-linked hypophosphatemia: a phase 3, single-arm, international trial. J Bone Miner Res.  https://doi.org/10.1002/jbmr.3843
  49. Ishikawa HO, Xu A, Ogura E, Manning G, Irvine KD (2012) The Raine syndrome protein FAM20C is a Golgi kinase that phosphorylates bio-mineralization proteins. PLoS One 7(8):e42988.  https://doi.org/10.1371/journal.pone.0042988CrossRefGoogle Scholar
  50. Ito N, Fukumoto S, Takeuchi Y, Yasuda T, Hasegawa Y, Takemoto F, Tajima T, Dobashi K, Yamazaki Y, Yamashita T, Fujita T (2005) Comparison of two assays for fibroblast growth factor (FGF)-23. J Bone Miner Metab 23(6):435–440.  https://doi.org/10.1007/s00774-005-0625-4CrossRefGoogle Scholar
  51. Ito N, Fukumoto S, Takeuchi Y, Takeda S, Suzuki H, Yamashita T, Fujita T (2007) Effect of acute changes of serum phosphate on fibroblast growth factor (FGF)23 levels in humans. J Bone Miner Metab 25(6):419–422.  https://doi.org/10.1007/s00774-007-0779-3CrossRefGoogle Scholar
  52. Itoh N, Ornitz DM (2004) Evolution of the Fgf and Fgfr gene families. Trends Genet 20(11):563–569.  https://doi.org/10.1016/j.tig.2004.08.007CrossRefGoogle Scholar
  53. Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Juppner H (2003) Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 348(17):1656–1663.  https://doi.org/10.1056/NEJMoa020881CrossRefGoogle Scholar
  54. Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H (2006) Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem 281(27):18370–18377.  https://doi.org/10.1074/jbc.M602469200CrossRefGoogle Scholar
  55. Kawakami K, Takeshita A, Furushima K, Miyajima M, Hatamura I, Kuro OM, Furuta Y, Sakaguchi K (2017) Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease. Sci Rep 7:40534.  https://doi.org/10.1038/srep40534CrossRefGoogle Scholar
  56. Kinoshita Y, Fukumoto S (2018) X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases: prospect for new treatment. Endocr Rev 39(3):274–291.  https://doi.org/10.1210/er.2017-00220CrossRefGoogle Scholar
  57. Kinoshita Y, Takashi Y, Ito N, Ikegawa S, Mano H, Ushiku T, Fukayama M, Nangaku M, Fukumoto S (2019) Ectopic expression of Klotho in fibroblast growth factor 23 (FGF23)-producing tumors that cause tumor-induced rickets/osteomalacia (TIO). Bone Rep 10:100192.  https://doi.org/10.1016/j.bonr.2018.100192CrossRefGoogle Scholar
  58. Kitanaka S, Takeyama K, Murayama A, Sato T, Okumura K, Nogami M, Hasegawa Y, Niimi H, Yanagisawa J, Tanaka T, Kato S (1998) Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med 338(10):653–661.  https://doi.org/10.1056/nejm199803053381004CrossRefGoogle Scholar
  59. 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(3):599–611.  https://doi.org/10.1016/j.kint.2017.02.014CrossRefGoogle Scholar
  60. 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(6655):45–51.  https://doi.org/10.1038/36285CrossRefGoogle Scholar
  61. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281(10):6120–6123.  https://doi.org/10.1074/jbc.C500457200CrossRefGoogle Scholar
  62. Lammoglia JJ, Mericq V (2009) Familial tumoral calcinosis caused by a novel FGF23 mutation: response to induction of tubular renal acidosis with acetazolamide and the non-calcium phosphate binder sevelamer. Horm Res 71(3):178–184.  https://doi.org/10.1159/000197876CrossRefGoogle Scholar
  63. Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, Juppner H, Jonsson KB (2004) 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 145(7):3087–3094.  https://doi.org/10.1210/en.2003-1768CrossRefGoogle Scholar
  64. Lee JC, Jeng YM, Su SY, Wu CT, Tsai KS, Lee CH, Lin CY, Carter JM, Huang JW, Chen SH, Shih SR, Marino-Enriquez A, Chen CC, Folpe AL, Chang YL, Liang CW (2015) Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. J Pathol 235(4):539–545.  https://doi.org/10.1002/path.4465CrossRefGoogle Scholar
  65. Lee JC, Su SY, Changou CA, Yang RS, Tsai KS, Collins MT, Orwoll ES, Lin CY, Chen SH, Shih SR, Lee CH, Oda Y, Billings SD, Li CF, Nielsen GP, Konishi E, Petersson F, Carpenter TO, Sittampalam K, Huang HY, Folpe AL (2016) Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Mod Pathol 29(11):1335–1346.  https://doi.org/10.1038/modpathol.2016.137CrossRefGoogle Scholar
  66. Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, Manor E, Buriakovsky S, Hadad Y, Goding J, Parvari R (2010) Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 86(2):273–278.  https://doi.org/10.1016/j.ajhg.2010.01.010CrossRefGoogle Scholar
  67. Li H, Martin A, David V, Quarles LD (2011) Compound deletion of Fgfr3 and Fgfr4 partially rescues the Hyp mouse phenotype. Am J Physiol Endocrinol Metab 300(3):E508–E517.  https://doi.org/10.1152/ajplung.zh5-5845-retr.2011CrossRefGoogle Scholar
  68. Lim YH, Ovejero D, Sugarman JS, Deklotz CM, Maruri A, Eichenfield LF, Kelley PK, Juppner H, Gottschalk M, Tifft CJ, Gafni RI, Boyce AM, Cowen EW, Bhattacharyya N, Guthrie LC, Gahl WA, Golas G, Loring EC, Overton JD, Mane SM, Lifton RP, Levy ML, Collins MT, Choate KA (2014) Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum Mol Genet 23(2):397–407.  https://doi.org/10.1093/hmg/ddt429CrossRefGoogle Scholar
  69. Lim YH, Ovejero D, Derrick KM, Collins MT, Choate KA (2016) Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy. J Am Acad Dermatol 75(2):420–427.  https://doi.org/10.1016/j.jaad.2015.11.012CrossRefGoogle Scholar
  70. Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD (2003) Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem 278(39):37419–37426.  https://doi.org/10.1074/jbc.M304544200CrossRefGoogle Scholar
  71. Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, Badenhoop K, Kaiser SM, Rittmaster RS, Shlossberg AH, Olivares JL, Loris C, Ramos FJ, Glorieux F, Vikkula M, Juppner H, Strom TM (2006) DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38(11):1248–1250.  https://doi.org/10.1038/ng1868CrossRefGoogle Scholar
  72. Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM (2010) Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet 86(2):267–272.  https://doi.org/10.1016/j.ajhg.2010.01.006CrossRefGoogle Scholar
  73. Lyles KW, Halsey DL, Friedman NE, Lobaugh B (1988) Correlations of serum concentrations of 1,25-dihydroxyvitamin D, phosphorus, and parathyroid hormone in tumoral calcinosis. J Clin Endocrinol Metab 67(1):88–92.  https://doi.org/10.1210/jcem-67-1-88CrossRefGoogle Scholar
  74. 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(13):5979–5983.  https://doi.org/10.1073/pnas.90.13.5979CrossRefGoogle Scholar
  75. Meyer RA Jr, Meyer MH, Gray RW (1989) Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice. J Bone Miner Res 4(4):493–500.  https://doi.org/10.1002/jbmr.5650040407CrossRefGoogle Scholar
  76. Minisola S, Peacock M, Fukumoto S, Cipriani C, Pepe J, Tella SH, Collins MT (2017) Tumour-induced osteomalacia. Nat Rev Dis Primers 3:17044.  https://doi.org/10.1038/nrdp.2017.44CrossRefGoogle Scholar
  77. Mishra SK, Kuchay MS, Sen IB, Garg A, Baijal SS, Mithal A (2019) Successful management of tumor-induced osteomalacia with radiofrequency ablation: a case series. JBMR Plus 3(7):e10178.  https://doi.org/10.1002/jbm4.10178CrossRefGoogle Scholar
  78. Murali SK, Roschger P, Zeitz U, Klaushofer K, Andrukhova O, Erben RG (2016) FGF23 regulates bone mineralization in a 1,25(OH)2 D3 and Klotho-independent manner. J Bone Miner Res 31(1):129–142.  https://doi.org/10.1002/jbmr.2606CrossRefGoogle Scholar
  79. Ohyama Y, Noshiro M, Okuda K (1991) Cloning and expression of cDNA encoding 25-hydroxyvitamin D3 24-hydroxylase. FEBS Lett 278(2):195–198.  https://doi.org/10.1016/0014-5793(91)80115-jCrossRefGoogle Scholar
  80. Olauson H, Lindberg K, Amin R, Sato T, Jia T, Goetz R, Mohammadi M, Andersson G, Lanske B, Larsson TE (2013) Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet 9(12):e1003975.  https://doi.org/10.1371/journal.pgen.1003975CrossRefGoogle Scholar
  81. Paquet M, Gauthe M, Zhang Yin J, Nataf V, Belissant O, Orcel P, Roux C, Talbot JN, Montravers F (2018) Diagnostic performance and impact on patient management of (68)Ga-DOTA-TOC PET/CT for detecting osteomalacia-associated tumours. Eur J Nucl Med Mol Imaging 45(10):1710–1720.  https://doi.org/10.1007/s00259-018-3971-xCrossRefGoogle Scholar
  82. Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA (2005) Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146(12):5358–5364.  https://doi.org/10.1210/en.2005-0777CrossRefGoogle Scholar
  83. Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, Bjerknes R (2013) Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res 28(6):1378–1385.  https://doi.org/10.1002/jbmr.1850CrossRefGoogle Scholar
  84. Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, Bianco P, Gehron Robey P (2003) FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 112(5):683–692.  https://doi.org/10.1172/jci18399CrossRefGoogle Scholar
  85. Roberts MS, Burbelo PD, Egli-Spichtig D, Perwad F, Romero CJ, Ichikawa S, Farrow E, Econs MJ, Guthrie LC, Collins MT, Gafni RI (2018) Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies. J Clin Invest 128(12):5368–5373.  https://doi.org/10.1172/jci122004CrossRefGoogle Scholar
  86. Rossaint J, Oehmichen J, Van Aken H, Reuter S, Pavenstadt HJ, Meersch M, Unruh M, Zarbock A (2016) FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J Clin Invest 126(3):962–974.  https://doi.org/10.1172/jci83470CrossRefGoogle Scholar
  87. Rowe PS, Kumagai Y, Gutierrez G, Garrett IR, Blacher R, Rosen D, Cundy J, Navvab S, Chen D, Drezner MK, Quarles LD, Mundy GR (2004) MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone 34(2):303–319.  https://doi.org/10.1016/j.bone.2003.10.005CrossRefGoogle Scholar
  88. Ruf N, Uhlenberg B, Terkeltaub R, Nurnberg P, Rutsch F (2005) The mutational spectrum of ENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI). Hum Mutat 25(1):98.  https://doi.org/10.1002/humu.9297CrossRefGoogle Scholar
  89. Saini RK, Kaneko I, Jurutka PW, Forster R, Hsieh A, Hsieh JC, Haussler MR, Whitfield GK (2013) 1,25-dihydroxyvitamin D(3) regulation of fibroblast growth factor-23 expression in bone cells: evidence for primary and secondary mechanisms modulated by leptin and interleukin-6. Calcif Tissue Int 92(4):339–353.  https://doi.org/10.1007/s00223-012-9683-5CrossRefGoogle Scholar
  90. Schouten BJ, Doogue MP, Soule SG, Hunt PJ (2009) Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia. Ann Clin Biochem 46(Pt 2):167–169.  https://doi.org/10.1258/acb.2008.008151CrossRefGoogle Scholar
  91. Segawa H, Kaneko I, Takahashi A, Kuwahata M, Ito M, Ohkido I, Tatsumi S, Miyamoto K (2002) Growth-related renal type II Na/Pi cotransporter. J Biol Chem 277(22):19665–19672.  https://doi.org/10.1074/jbc.M200943200CrossRefGoogle Scholar
  92. Shalhoub V, Shatzen EM, Ward SC, Davis J, Stevens J, Bi V, Renshaw L, Hawkins N, Wang W, Chen C, Tsai MM, Cattley RC, Wronski TJ, Xia X, Li X, Henley C, Eschenberg M, Richards WG (2012) FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J Clin Invest 122(7):2543–2553.  https://doi.org/10.1172/jci61405CrossRefGoogle Scholar
  93. Shawar SM, Ramadan AR, Ali BR, Alghamdi MA, John A, Hudaib FM (2016) FGF23-S129F mutant bypasses ER/Golgi to the circulation of hyperphosphatemic familial tumoral calcinosis patients. Bone 93:187–195.  https://doi.org/10.1016/j.bone.2015.11.015CrossRefGoogle Scholar
  94. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2001) Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 98(11):6500–6505.  https://doi.org/10.1073/pnas.101545198CrossRefGoogle Scholar
  95. Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2002) Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143(8):3179–3182.  https://doi.org/10.1210/endo.143.8.8795CrossRefGoogle Scholar
  96. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T (2004a) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19(3):429–435.  https://doi.org/10.1359/jbmr.0301264CrossRefGoogle Scholar
  97. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T (2004b) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113(4):561–568.  https://doi.org/10.1172/jci19081CrossRefGoogle Scholar
  98. 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(5):F1088–F1095.  https://doi.org/10.1152/ajprenal.00474.2004CrossRefGoogle Scholar
  99. Shimizu Y, Tada Y, Yamauchi M, Okamoto T, Suzuki H, Ito N, Fukumoto S, Sugimoto T, Fujita T (2009) Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: another form of FGF23-related hypophosphatemia. Bone 45(4):814–816.  https://doi.org/10.1016/j.bone.2009.06.017CrossRefGoogle Scholar
  100. Simpson MA, Hsu R, Keir LS, Hao J, Sivapalan G, Ernst LM, Zackai EH, Al-Gazali LI, Hulskamp G, Kingston HM, Prescott TE, Ion A, Patton MA, Murday V, George A, Crosby AH (2007) Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am J Hum Genet 81(5):906–912.  https://doi.org/10.1086/522240CrossRefGoogle Scholar
  101. Singh S, Grabner A, Yanucil C, Schramm K, Czaya B, Krick S, Czaja MJ, Bartz R, Abraham R, Di Marco GS, Brand M, Wolf M, Faul C (2016) Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int 90(5):985–996.  https://doi.org/10.1016/j.kint.2016.05.019CrossRefGoogle Scholar
  102. Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, Juppner H, Lanske B (2004) Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23(7):421–432.  https://doi.org/10.1016/j.matbio.2004.09.007CrossRefGoogle Scholar
  103. 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(15):5520–5525.  https://doi.org/10.1073/pnas.1402218111CrossRefGoogle Scholar
  104. Takashi Y, Kosako H, Sawatsubashi S, Kinoshita Y, Ito N, Tsoumpra MK, Nangaku M, Abe M, Matsuhisa M, Kato S, Matsumoto T, Fukumoto S (2019) Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation. Proc Natl Acad Sci U S A 116(23):11418–11427.  https://doi.org/10.1073/pnas.1815166116CrossRefGoogle Scholar
  105. Takeshita A, Kawakami K, Furushima K, Miyajima M, Sakaguchi K (2018) Central role of the proximal tubular αKlotho/FGF receptor complex in FGF23-regulated phosphate and vitamin D metabolism. Sci Rep 8(1):6917.  https://doi.org/10.1038/s41598-018-25087-3CrossRefGoogle Scholar
  106. Takeuchi Y, Suzuki H, Ogura S, Imai R, Yamazaki Y, Yamashita T, Miyamoto Y, Okazaki H, Nakamura K, Nakahara K, Fukumoto S, Fujita T (2004) Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia. J Clin Endocrinol Metab 89(8):3979–3982.  https://doi.org/10.1210/jc.2004-0406CrossRefGoogle Scholar
  107. Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S (1997) 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science 277(5333):1827–1830.  https://doi.org/10.1126/science.277.5333.1827CrossRefGoogle Scholar
  108. Takeyari S, Yamamoto T, Kinoshita Y, Fukumoto S, Glorieux FH, Michigami T, Hasegawa K, Kitaoka T, Kubota T, Imanishi Y, Shimotsuji T, Ozono K (2014) Hypophosphatemic osteomalacia and bone sclerosis caused by a novel homozygous mutation of the FAM20C gene in an elderly man with a mild variant of Raine syndrome. Bone 67:56–62.  https://doi.org/10.1016/j.bone.2014.06.026CrossRefGoogle Scholar
  109. Tanaka Y, Deluca HF (1973) The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys 154(2):566–574.  https://doi.org/10.1016/0003-9861(73)90010-6CrossRefGoogle Scholar
  110. Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, Khamaysi Z, Behar D, Petronius D, Friedman V, Zelikovic I, Raimer S, Metzker A, Richard G, Sprecher E (2004) Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 36(6):579–581.  https://doi.org/10.1038/ng1358CrossRefGoogle Scholar
  111. Turner AJ, Tanzawa K (1997) Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX. FASEB J 11(5):355–364.  https://doi.org/10.1096/fasebj.11.5.9141502CrossRefGoogle Scholar
  112. Tutton S, Olson E, King D, Shaker JL (2012) Successful treatment of tumor-induced osteomalacia with CT-guided percutaneous ethanol and cryoablation. J Clin Endocrinol Metab 97(10):3421–3425.  https://doi.org/10.1210/jc.2012-1719CrossRefGoogle Scholar
  113. 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(7120):770–774.  https://doi.org/10.1038/nature05315CrossRefGoogle Scholar
  114. Wang X, Wang S, Li C, Gao T, Liu Y, Rangiani A, Sun Y, Hao J, George A, Lu Y, Groppe J, Yuan B, Feng JQ, Qin C (2012) Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS Genet 8(5):e1002708.  https://doi.org/10.1371/journal.pgen.1002708CrossRefGoogle Scholar
  115. Wasserman H, Ikomi C, Hafberg ET, Miethke AG, Bove KE, Backeljauw PF (2016) Two case reports of FGF23-induced hypophosphatemia in childhood biliary atresia. Pediatrics 138(2):e20154453.  https://doi.org/10.1542/peds.2015-4453CrossRefGoogle Scholar
  116. 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(6):2079–2086.  https://doi.org/10.1046/j.1523-1755.2001.00064.xCrossRefGoogle Scholar
  117. White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, McKeown C, Fitzpatrick D, Yu K, Ornitz DM, Econs MJ (2005) Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 76(2):361–367.  https://doi.org/10.1086/427956CrossRefGoogle Scholar
  118. Winzenberg T, Jones G (2013) Vitamin D and bone health in childhood and adolescence. Calcif Tissue Int 92(2):140–150.  https://doi.org/10.1007/s00223-012-9615-4CrossRefGoogle Scholar
  119. Wohrle S, Henninger C, Bonny O, Thuery A, Beluch N, Hynes NE, Guagnano V, Sellers WR, Hofmann F, Kneissel M, Graus Porta D (2013) Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res 28(4):899–911.  https://doi.org/10.1002/jbmr.1810CrossRefGoogle Scholar
  120. Wolf M (2010) Forging forward with 10 burning questions on FGF23 in kidney disease. J Am Soc Nephrol 21(9):1427–1435.  https://doi.org/10.1681/asn.2009121293CrossRefGoogle Scholar
  121. Wolf M, Koch TA, Bregman DB (2013) Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res 28(8):1793–1803.  https://doi.org/10.1002/jbmr.1923CrossRefGoogle Scholar
  122. Xiao Z, Riccardi D, Velazquez HA, Chin AL, Yates CR, Carrick JD, Smith JC, Baudry J, Quarles LD (2016) A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia. Sci Signal 9(455):ra113.  https://doi.org/10.1126/scisignal.aaf5034CrossRefGoogle Scholar
  123. Yamashita T, Yoshioka M, Itoh N (2000) Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 277(2):494–498.  https://doi.org/10.1006/bbrc.2000.3696CrossRefGoogle Scholar
  124. Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S (2002) Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 87(11):4957–4960.  https://doi.org/10.1210/jc.2002-021105CrossRefGoogle Scholar
  125. Yamazaki Y, Tamada T, Kasai N, Urakawa I, Aono Y, Hasegawa H, Fujita T, Kuroki R, Yamashita T, Fukumoto S, Shimada T (2008) Anti-FGF23 neutralizing antibodies show the physiological role and structural features of FGF23. J Bone Miner Res 23(9):1509–1518.  https://doi.org/10.1359/jbmr.080417CrossRefGoogle Scholar
  126. 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(2):683–689.  https://doi.org/10.1210/endo.143.2.8657CrossRefGoogle Scholar
  127. Yu X, Ibrahimi OA, Goetz R, Zhang F, Davis SI, Garringer HJ, Linhardt RJ, Ornitz DM, Mohammadi M, White KE (2005) Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology 146(11):4647–4656.  https://doi.org/10.1210/en.2005-0670CrossRefGoogle Scholar
  128. Yuan B, Takaiwa M, Clemens TL, Feng JQ, Kumar R, Rowe PS, Xie Y, Drezner MK (2008) Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest 118(2):722–734.  https://doi.org/10.1172/jci32702CrossRefGoogle Scholar
  129. Yuan B, Feng JQ, Bowman S, Liu Y, Blank RD, Lindberg I, Drezner MK (2013) Hexa-D-arginine treatment increases 7B2⋅PC2 activity in hyp-mouse osteoblasts and rescues the HYP phenotype. J Bone Miner Res 28(1):56–72.  https://doi.org/10.1002/jbmr.1738CrossRefGoogle Scholar
  130. Zhang MY, Ranch D, Pereira RC, Armbrecht HJ, Portale AA, Perwad F (2012) Chronic inhibition of ERK1/2 signaling improves disordered bone and mineral metabolism in hypophosphatemic (Hyp) mice. Endocrinology 153(4):1806–1816.  https://doi.org/10.1210/en.2011-1831CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Seiji Fukumoto
    • 1
  1. 1.Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical SciencesTokushima UniversityTokushimaJapan

Personalised recommendations