Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology. 2002;143:3179–82. https://doi.org/10.1210/endo.143.8.8795.
CAS
Article
PubMed
Google Scholar
White KE, Evans WE, O’Riordan JLH, Speer MC, Econs MJ, Lorenz-Depiereux B, et al. ADHR-Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26:345–8.
CAS
Article
Google Scholar
White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 2001;60:2079–86. https://doi.org/10.1046/j.1523-1755.2001.00064.x.
CAS
Article
PubMed
Google Scholar
•• Bon N, et al. Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2. Mol Metab. 2018;11:197–204. https://doi.org/10.1016/j.molmet.2018.02.007 This reference supports that the phosphate transporter PiT2 is required for producing FGF23 in response to changes in extracellular phosphate.
CAS
Article
PubMed
PubMed Central
Google Scholar
Perwad F, et al. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology. 2005;146:5358–64. https://doi.org/10.1210/en.2005-0777.
CAS
Article
PubMed
Google Scholar
Bon N, Couasnay G, Bourgine A, Sourice S, Beck-Cormier S, Guicheux J, et al. Phosphate (Pi)-regulated heterodimerization of the high-affinity sodium-dependent Pi transporters PiT1/Slc20a1 and PiT2/Slc20a2 underlies extracellular Pi sensing independently of Pi uptake. J Biol Chem. 2018;293:2102–14. https://doi.org/10.1074/jbc.M117.807339.
CAS
Article
PubMed
Google Scholar
Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, et al. 1alpha,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol. 2005;289:G1036–42. https://doi.org/10.1152/ajpgi.00243.2005.
CAS
Article
PubMed
Google Scholar
Liu S, et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol. 2006;17:1305–15. https://doi.org/10.1681/ASN.2005111185.
CAS
Article
PubMed
Google Scholar
Kaneko I, Saini RK, Griffin KP, Whitfield GK, Haussler MR, Jurutka PW. FGF23 gene regulation by 1,25-dihydroxyvitamin D: opposing effects in adipocytes and osteocytes. J Endocrinol. 2015;226:155–66. https://doi.org/10.1530/JOE-15-0225.
CAS
Article
PubMed
PubMed Central
Google Scholar
Shimada T, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19:429–35.
CAS
Article
Google Scholar
Clinkenbeard EL, Farrow EG, Summers LJ, Cass TA, Roberts JL, Bayt CA, et al. Neonatal iron deficiency causes abnormal phosphate metabolism by elevating FGF23 in normal and ADHR mice. J Bone Miner Res. 2014;29:361–9. https://doi.org/10.1002/jbmr.2049.
CAS
Article
PubMed
PubMed Central
Google Scholar
Zhang Q, Doucet M, Tomlinson RE, Han X, Quarles LD, Collins MT, et al. The hypoxia-inducible factor-1alpha activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia. Bone Res. 2016;4:16011. https://doi.org/10.1038/boneres.2016.11.
Article
PubMed
PubMed Central
Google Scholar
Flamme I, Ellinghaus P, Urrego D, Kruger T. FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase. PLoS One. 2017;12:e0186979. https://doi.org/10.1371/journal.pone.0186979.
CAS
Article
PubMed
PubMed Central
Google Scholar
David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2015;22:1020–32. https://doi.org/10.1038/ki.2015.290.
CAS
Article
Google Scholar
Ito N, Wijenayaka AR, Prideaux M, Kogawa M, Ormsby RT, Evdokiou A, et al. Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli. Mol Cell Endocrinol. 2015;399:208–18. https://doi.org/10.1016/j.mce.2014.10.007.
CAS
Article
PubMed
Google Scholar
Farrow EG, Yu X, Summers LJ, Davis SI, Fleet JC, Allen MR, et al. 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. 2011;108:E1146–55. https://doi.org/10.1073/pnas.1110905108.
CAS
Article
PubMed
PubMed Central
Google Scholar
Rabadi S, Udo I, Leaf DE, Waikar S, Christov M. Acute blood loss stimulates fibroblast growth factor 23 production. Am J Physiol Ren Physiol. 2017;314(1):F132–9. ajprenal 00081.02017. https://doi.org/10.1152/ajprenal.00081.2017.
CAS
Article
Google Scholar
Clinkenbeard EL, Hanudel MR, Stayrook KR, Appaiah HN, Farrow EG, Cass TA, et al. Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow. Haematologica. 2017;102:e427–30. https://doi.org/10.3324/haematol.2017.167882.
CAS
Article
PubMed
PubMed Central
Google Scholar
Hanudel MR, Eisenga MF, Rappaport M, Chua K, Qiao B, Jung G, et al. Effects of erythropoietin on fibroblast growth factor 23 in mice and humans. Nephrol Dial Transplant. 2018. https://doi.org/10.1093/ndt/gfy189.
Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013;28:1793–803. https://doi.org/10.1002/jbmr.1923.
CAS
Article
PubMed
Google Scholar
Shimizu Y, Tada Y, Yamauchi M, Okamoto T, Suzuki H, Ito N, et al. Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: another form of FGF23-related hypophosphatemia. Bone. 2009;45:814–6. https://doi.org/10.1016/j.bone.2009.06.017.
CAS
Article
PubMed
Google Scholar
Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab. 2009;94:2332–7. https://doi.org/10.1210/jc.2008-2396.
CAS
Article
PubMed
Google Scholar
Smith RC, O’Bryan LM, Farrow EG, Summers LJ, Clinkenbeard EL, Roberts JL, et al. Circulating alphaKlotho influences phosphate handling by controlling FGF23 production. J Clin Invest. 2012;122:4710–5. https://doi.org/10.1172/JCI64986.
CAS
Article
PubMed
PubMed Central
Google Scholar
Hum JM, et al. Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble Klotho. J Am Soc Nephrol. 2016;28:1162–74. https://doi.org/10.1681/ASN.2015111266.
Article
PubMed
PubMed Central
Google Scholar
Krajisnik T, Bjorklund P, Marsell R, Ljunggren O, Akerstrom G, Jonsson KB, et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol. 2007;195:125–31. https://doi.org/10.1677/JOE-07-0267.
CAS
Article
PubMed
Google Scholar
Knab VM, Corbin B, Andrukhova O, Hum JM, Ni P, Rabadi S, et al. Acute parathyroid hormone injection increases C-terminal but not intact fibroblast growth factor 23 levels. Endocrinology. 2017;158:1130–9. https://doi.org/10.1210/en.2016-1451.
Article
PubMed
PubMed Central
Google Scholar
Kobayashi K, et al. Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism. Eur J Endocrinol. 2006;154:93–9. https://doi.org/10.1530/eje.1.02053.
CAS
Article
PubMed
Google Scholar
Ben-Dov IZ, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest. 2007;117:4003–8. https://doi.org/10.1172/JCI32409.
CAS
Article
PubMed
PubMed Central
Google Scholar
David V, et al. Calcium regulates FGF-23 expression in bone. Endocrinology. 2013;154:4469–82. https://doi.org/10.1210/en.2013-1627.
CAS
Article
PubMed
PubMed Central
Google Scholar
Clinkenbeard EL, Cass TA, Ni P, Hum JM, Bellido T, Allen MR, et al. Conditional deletion of murine Fgf23: interruption of the normal skeletal responses to phosphate challenge and rescue of genetic hypophosphatemia. J Bone Miner Res. 2016;31:1247–57. https://doi.org/10.1002/jbmr.2792.
CAS
Article
PubMed
PubMed Central
Google Scholar
•• Onal M, et al. A novel distal enhancer mediates inflammation-, PTH-, and early onset murine kidney disease-induced expression of the mouse Fgf23 gene. JBMR Plus. 2018;2:32–47. https://doi.org/10.1002/jbm4.10023 This citation demonstrates that distal portions of the FGF23 promoter may regulate FGF23 under specific physiological and disease conditions.
CAS
Article
PubMed
Google Scholar
Shimada T, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest. 2004;113:561–8. https://doi.org/10.1172/JCI19081.
CAS
Article
PubMed
PubMed Central
Google Scholar
Fleet JC, Replogle RA, Reyes-Fernandez P, Wang L, Zhang M, Clinkenbeard EL, et al. Gene-by-diet interactions affect serum 1,25-dihydroxyvitamin D levels in male BXD recombinant inbred mice. Endocrinology. 2016;157:470–81. https://doi.org/10.1210/en.2015-1786.
CAS
Article
PubMed
Google Scholar
Gravesen E, Mace ML, Hofman-Bang J, Olgaard K, Lewin E. Circulating FGF23 levels in response to acute changes in plasma Ca(2+). Calcif Tissue Int. 2014;95:46–53. https://doi.org/10.1007/s00223-014-9861-8.
CAS
Article
PubMed
Google Scholar
Rodriguez-Ortiz ME, et al. Calcium deficiency reduces circulating levels of FGF23. J Am Soc Nephrol. 2012;23:1190–7. https://doi.org/10.1681/ASN.2011101006.
CAS
Article
PubMed
PubMed Central
Google Scholar
Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770–4. https://doi.org/10.1038/nature05315.
CAS
Article
PubMed
PubMed Central
Google Scholar
Kawata T, et al. Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism. J Am Soc Nephrol. 2007;18:2683–8. https://doi.org/10.1681/ASN.2006070783.
CAS
Article
PubMed
Google Scholar
Meir T, Durlacher K, Pan Z, Amir G, Richards WG, Silver J, et al. Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription. Kidney Int. 2014;86:1106–15. https://doi.org/10.1038/ki.2014.215.
CAS
Article
PubMed
Google Scholar
Hanks LJ, Casazza K, Judd SE, Jenny NS, Gutierrez OM. Associations of fibroblast growth factor-23 with markers of inflammation, insulin resistance and obesity in adults. PLoS One. 2015;10:e0122885. https://doi.org/10.1371/journal.pone.0122885.
CAS
Article
PubMed
PubMed Central
Google Scholar
Holecki M, et al. Inflammation but not obesity or insulin resistance is associated with increased plasma fibroblast growth factor 23 concentration in the elderly. Clin Endocrinol. 2015;82:900–9. https://doi.org/10.1111/cen.12759.
CAS
Article
Google Scholar
Eren M, Place AT, Thomas PM, Flevaris P, Miyata T, Vaughan DE. PAI-1 is a critical regulator of FGF23 homeostasis. Sci Adv. 2017;3:e1603259. https://doi.org/10.1126/sciadv.1603259.
CAS
Article
PubMed
PubMed Central
Google Scholar
Nam KH, Kim H, An SY, Lee M, Cha MU, Park JT, et al. Circulating fibroblast growth factor-23 levels are associated with an increased risk of anemia development in patients with nondialysis chronic kidney disease. Sci Rep. 2018;8:7294. https://doi.org/10.1038/s41598-018-25439-z.
CAS
Article
PubMed
PubMed Central
Google Scholar
Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, et al. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A. 2014;111:5520–5. https://doi.org/10.1073/pnas.1402218111.
CAS
Article
PubMed
PubMed Central
Google Scholar
Kato K, et al. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem. 2006;281:18370–7. https://doi.org/10.1074/jbc.M602469200.
CAS
Article
PubMed
Google Scholar
Ichikawa S, et al. Genetic rescue of glycosylation-deficient Fgf23 in the Galnt3 knockout mouse. Endocrinology. 2014;155:3891–8. https://doi.org/10.1210/en.2014-1199.
CAS
Article
PubMed
PubMed Central
Google Scholar
Raine J, Winter RM, Davey A, Tucker SM. Unknown syndrome: microcephaly, hypoplastic nose, exophthalmos, gum hyperplasia, cleft palate, low set ears, and osteosclerosis. J Med Genet. 1989;26:786–8.
CAS
Article
Google Scholar
Simpson MA, Hsu R, Keir LS, Hao J, Sivapalan G, Ernst LM, et al. Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am J Hum Genet. 2007;81:906–12. https://doi.org/10.1086/522240.
CAS
Article
PubMed
PubMed Central
Google Scholar
Wang X, Wang S, Li C, Gao T, Liu Y, Rangiani A, et al. Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS Genet. 2012;8:e1002708. https://doi.org/10.1371/journal.pgen.1002708.
CAS
Article
PubMed
PubMed Central
Google Scholar
Carpenter TO, et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014;124:1587–97. https://doi.org/10.1172/JCI72829.
CAS
Article
PubMed
PubMed Central
Google Scholar
Imel EA, et al. Prolonged correction of serum phosphorus in adults with X-linked hypophosphatemia using monthly doses of KRN23. J Clin Endocrinol Metab. 2015;100:2565–73. https://doi.org/10.1210/jc.2015-1551.
CAS
Article
PubMed
PubMed Central
Google Scholar
Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart A, et al. Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med. 2018;378:1987–98. https://doi.org/10.1056/NEJMoa1714641.
CAS
Article
PubMed
Google Scholar
Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima YI. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun. 1998;242:626–30.
CAS
Article
Google Scholar
•• Chen G, et al. alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature. 2018;553:461–6. https://doi.org/10.1038/nature25451 This paper reported the triple crystal structure of FGF23-KL-FGFR1, and tests the idea that the soluble form of KL can mediate FGF23 bioactivity in tissue where KL has limited expression.
CAS
Article
PubMed
PubMed Central
Google Scholar
Imura A, et al. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett. 2004;565:143–7. https://doi.org/10.1016/j.febslet.2004.03.090S0014579304003990.
CAS
Article
PubMed
Google Scholar
Hu MC, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22:124–36. https://doi.org/10.1681/ASN.2009121311.
CAS
Article
PubMed
PubMed Central
Google Scholar
Gattineni J, Alphonse P, Zhang Q, Mathews N, Bates CM, Baum M. Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am J Physiol Ren Physiol. 2014;306:F351–8. https://doi.org/10.1152/ajprenal.00232.2013.
CAS
Article
Google Scholar
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.
CAS
Article
Google Scholar
Farrow EG, Davis SI, Summers LJ, White KE. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol. 2009;20:955–60. https://doi.org/10.1681/ASN.2008070783.
CAS
Article
PubMed
PubMed Central
Google Scholar
Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren Ö, Tenenhouse HS, et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology. 2004;145:3087–94.
CAS
Article
Google Scholar
Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A. 2001;98:6500–5.
CAS
Article
Google Scholar
Olauson H, et al. Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism. J Am Soc Nephrol. 2012;23:1641–51. https://doi.org/10.1681/ASN.2012010048.
CAS
Article
PubMed
PubMed Central
Google Scholar
Ide N, Olauson H, Sato T, Densmore MJ, Wang H, Hanai JI, et al. In vivo evidence for a limited role of proximal tubular Klotho in renal phosphate handling. Kidney Int. 2016;90:348–62. https://doi.org/10.1016/j.kint.2016.04.009.
CAS
Article
PubMed
Google Scholar
Takeshita A, Kawakami K, Furushima K, Miyajima M, Sakaguchi K. Central role of the proximal tubular alphaKlotho/FGF receptor complex in FGF23-regulated phosphate and vitamin D metabolism. Sci Rep. 2018;8:6917. https://doi.org/10.1038/s41598-018-25087-3.
CAS
Article
PubMed
PubMed Central
Google Scholar
Ide N, Ye R, Courbebaisse M, Olauson H, Densmore MJ, Larsson TE, et al. In vivo evidence for an interplay of FGF23/Klotho/PTH axis on the phosphate handling in renal proximal tubules. Am J Physiol Ren Physiol. 2018;315:F1261–70. https://doi.org/10.1152/ajprenal.00650.2017.
Article
Google Scholar
Andrukhova O, Slavic S, Smorodchenko A, Zeitz U, Shalhoub V, Lanske B, et al. FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med. 2014;6:744–59. https://doi.org/10.1002/emmm.201303716.
CAS
Article
PubMed
PubMed Central
Google Scholar
Chang Q, et al. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science. 2005;310:490–3.
CAS
Article
Google Scholar
Andrukhova O, et al. FGF23 promotes renal calcium reabsorption through the TRPV5 channel. EMBO J. 2013;33:229–46. https://doi.org/10.1002/embj.201284188.
CAS
Article
Google Scholar
Olauson H, Mencke R, Hillebrands JL, Larsson TE. Tissue expression and source of circulating alphaKlotho. Bone. 2017;100:19–35. https://doi.org/10.1016/j.bone.2017.03.043.
CAS
Article
PubMed
Google Scholar
Faul C, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121:4393–408. https://doi.org/10.1172/JCI46122.
CAS
Article
PubMed
PubMed Central
Google Scholar
Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, et al. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab. 2015;22:1020–32. https://doi.org/10.1016/j.cmet.2015.09.002.
CAS
Article
PubMed
PubMed Central
Google Scholar
•• Grabner A, et al. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Sci Rep. 2017;7:1993. https://doi.org/10.1038/s41598-017-02068-6 This paper showed that the cardiac hypertrophy due to high-phopshate diet and elevated FGF23 could be reversed by lowering serum phopshate.
CAS
Article
PubMed
PubMed Central
Google Scholar
Czaya B, et al. Induction of an inflammatory response in primary hepatocyte cultures from mice. J Visual Exp. 2017. https://doi.org/10.3791/55319.
Singh S, Grabner A, Yanucil C, Schramm K, Czaya B, Krick S, et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int. 2016;90:985–96. https://doi.org/10.1016/j.kint.2016.05.019.
CAS
Article
PubMed
PubMed Central
Google Scholar
Liu ES, Thoonen R, Petit E, Yu B, Buys ES, Scherrer-Crosbie M, et al. Increased circulating FGF23 does not lead to cardiac hypertrophy in the male Hyp mouse model of XLH. Endocrinology. 2018;159:2165–72. https://doi.org/10.1210/en.2018-00174.
Article
PubMed
Google Scholar
Neuburg S, Dussold C, Gerber C, Wang X, Francis C, Qi L, et al. Genetic background influences cardiac phenotype in murine chronic kidney disease. Nephrol Dial Transplant. 2018;33:1129–37. https://doi.org/10.1093/ndt/gfx332.
Article
PubMed
Google Scholar