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.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
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.2012.05.015
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.201303716
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.201284188
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.090509
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.275
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.2005-0301
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.2013-2813
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/jci119276
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/jci32409
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/ddi034
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/cwr182
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/10.1086/499409
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/jci18563
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.2014.04.016
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.94.2.9988
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.0712361105
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.2004-0357
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.340
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/jci72829
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/NEJMoa1714641
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/nature25451
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/ng1095-130
ADHR Consortium (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26(3):345–348. https://doi.org/10.1038/81664
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.2015.290
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-x
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.2008.02.014
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.1110905108
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/ng1905
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.2004-1039
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):1–30
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.061105
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.2018.00048
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/s00774-011-0298-0
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.90742.2008
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.00740.2010
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/nrm3528
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.0902006107
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.2015.09.002
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/NEJMoa0706130
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/s41581-019-0152-5
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/10.1002/1873-3468.12040
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.2010.313
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.2849209
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/jci31330
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.070107
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)30654-3
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.3475
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
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.0042988
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/s00774-005-0625-4
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/s00774-007-0779-3
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.2004.08.007
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/NEJMoa020881
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.M602469200
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/srep40534
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.2017-00220
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.2018.100192
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/nejm199803053381004
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.2017.02.014
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/10.1038/36285
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.C500457200
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/10.1159/000197876
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.2003-1768
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.4465
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.2016.137
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.2010.01.010
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.2011
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/ddt429
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.2015.11.012
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.M304544200
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/ng1868
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.2010.01.006
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-67-1-88
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.90.13.5979
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.5650040407
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.2017.44
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/jbm4.10178
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.2606
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-j
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.1003975
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-x
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.2005-0777
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.1850
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/jci18399
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/jci122004
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/jci83470
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.2003.10.005
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.9297
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/s00223-012-9683-5
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.2008.008151
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.M200943200
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/jci61405
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.2015.11.015
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.101545198
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.143.8.8795
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.0301264
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/jci19081
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.00474.2004
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.2009.06.017
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/10.1086/522240
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.2016.05.019
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.2004.09.007
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.1402218111
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.1815166116
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/s41598-018-25087-3
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.2004-0406
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.277.5333.1827
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.2014.06.026
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)90010-6
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/ng1358
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.11.5.9141502
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.2012-1719
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/nature05315
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.1002708
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.2015-4453
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.x
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/10.1086/427956
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/s00223-012-9615-4
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.1810
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.2009121293
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.1923
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.aaf5034
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.2000.3696
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.2002-021105
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.080417
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.143.2.8657
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.2005-0670
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/jci32702
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.1738
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.2011-1831
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Fukumoto, S. (2019). FGF23 and Bone and Mineral Metabolism. In: Stern, P.H. (eds) Bone Regulators and Osteoporosis Therapy. Handbook of Experimental Pharmacology, vol 262. Springer, Cham. https://doi.org/10.1007/164_2019_330
Download citation
DOI: https://doi.org/10.1007/164_2019_330
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-57377-5
Online ISBN: 978-3-030-57378-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)