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Fibroblast Growth Factor 23: Mechanisms of Action and Regulation

Toshimi Michigami


                Fibroblast growth factor 23 (FGF23) is a central regulator in mineral metabolism. It is produced mainly by osteocytes in the bone and exerts its effects on distant organs in an endocrine manner. FGF23 generally requires a transmembrane protein named aKlotho to evoke its signal via an FGF receptor (FGFR). In the kidney, FGF23 increases the renal phosphate excretion and decreases the production of 1,25-dihydroxyvitamin D [1,25(OH)2D]. In the parathyroid gland, it suppresses the secretion of parathyroid hormone (PTH). The placenta also expresses both FGFR1 and aKlotho, and an elevated level of maternal FGF23 induces the placental expression of 25-hydroxyvitamin D-24-hydroxylase, affecting fetal vitamin D metabolism. Pathologically elevated levels of FGF23 may exert its effects even on the tissues without aKlotho expression, such as myocardium. Excessive action of FGF23 of various causes leads to hypophosphatemic rickets/osteomalacia, while its impaired action results in hyperphosphatemia and ectopic calcification. Some of the molecules responsible for hereditary hypophosphatemic rickets/osteomalacia reside in the osteocytes and function as local regulators of the production and/or activity of FGF23. The FGF23 expression is controlled by systemic factors also, among which 1,25(OH)2D appears to be a principal regulator. In chronic kidney disease (CKD), FGF23 levels begin to increase from the early stages, although the underlying mechanism still remains unclear. The elevated FGF23 levels in CKD have been shown to be associated with poor outcomes. Elucidation of the mechanism for action and regulation of FGF23 will contribute to the development of new strategies for diagnosis and treatment of the diseases with impaired mineral metabolism. 


FGF23; αKlotho; osteocytes; hypophosphatemic rickets; chronic kidney disease

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ADHR-CONSORTIUM. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26(3):345-8.

Andrukhova O, Smorodchenko A, Egerbacher M, Streicher C, Zeitz U, Goetz R et al. FGF23 promotes renal calcium reabsorption through the TRPV5 channel. The EMBO journal. 2014;33(3):229-46. doi:10.1002/embj.201284188.

Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab. 2006;91(8):3144-9. doi:10.1210/jc.2006-0021.

Araya K, Fukumoto S, Backenroth R, Takeuchi Y, Nakayama K, Ito N et al. A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab. 2005;90(10):5523-7. doi:jc.2005-0301 [pii] 10.1210/jc.2005-0301 [doi].

Arnaud E, Touriol C, Boutonnet C, Gensac MC, Vagner S, Prats H et al. A new 34-kilodalton isoform of human fibroblast growth factor 2 is cap dependently synthesized by using a non-AUG start codon and behaves as a survival factor. Molecular and cellular biology. 1999;19(1):505-14.

Arnlov J, Carlsson AC, Sundstrom J, Ingelsson E, Larsson A, Lind L et al. Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney international. 2013;83(1):160-6. doi:10.1038/ki.2012.327.

Bass J, Takahashi JS. Circadian integration of metabolism and energetics. Science. 2010;330(6009):1349-54. doi:10.1126/science.1195027.

Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG et al. Pex/PEX tissue distribution and evidence for a deletion in the 3' region of the Pex gene in X-linked hypophosphatemic mice. The Journal of clinical investigation. 1997;99(6):1200-9. doi:10.1172/JCI119276 [doi].

Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M et al. The parathyroid is a target organ for FGF23 in rats. The Journal of clinical investigation. 2007;117(12):4003-8. doi:10.1172/JCI32409 [doi].

Benet-Pages A, Lorenz-Depiereux B, Zischka H, White KE, Econs MJ, Strom TM. FGF23 is processed by proprotein convertases but not by PHEX. Bone. 2004;35(2):455-62. doi:10.1016/j.bone.2004.04.002 [doi] S8756328204001619 [pii].

Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Human molecular genetics. 2005;14(3):385-90. doi:10.1093/hmg/ddi034.

Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2006;21(8):1187-96. doi:10.1359/jbmr.060507.

Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician's guide to X-linked hypophosphatemia. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011;26(7):1381-8. doi:10.1002/jbmr.340 [doi].

Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. The Journal of clinical investigation. 2014;124(4):1587-97. doi:10.1172/JCI72829.

Chlebova K, Bryja V, Dvorak P, Kozubik A, Wilcox WR, Krejci P. High molecular weight FGF2: the biology of a nuclear growth factor. Cellular and molecular life sciences : CMLS. 2009;66(2):225-35. doi:10.1007/s00018-008-8440-4.

Christov M, Waikar SS, Pereira RC, Havasi A, Leaf DE, Goltzman D et al. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney international. 2013;84(4):776-85. doi:10.1038/ki.2013.150.

Dai B, David V, Martin A, Huang J, Li H, Jiao Y et al. A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PloS one. 2012;7(9):e44161. doi:10.1371/journal.pone.0044161.

Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab. 1997;82(2):674-81. doi:10.1210/jcem.82.2.3765.

Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine & growth factor reviews. 2005;16(2):139-49. doi:10.1016/j.cytogfr.2005.01.001.

Farrow EG, Davis SI, Summers LJ, White KE. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. Journal of the American Society of Nephrology : JASN. 2009;20(5):955-60. doi:ASN.2008070783 [pii] 10.1681/ASN.2008070783 [doi].

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. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(46):E1146-55. doi:1110905108 [pii] 10.1073/pnas.1110905108 [doi].

Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T et al. FGF23 induces left ventricular hypertrophy. The Journal of clinical investigation. 2011;121(11):4393-408. doi:46122 [pii] 10.1172/JCI46122 [doi].

Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006;38(11):1310-5. doi:ng1905 [pii] 10.1038/ng1905 [doi].

Ferrari SL, Bonjour JP, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab. 2005;90(3):1519-24. doi:jc.2004-1039 [pii] 10.1210/jc.2004-1039 [doi].

Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. Journal of the American Society of Nephrology : JASN. 2007;18(9):2600-8. doi:10.1681/ASN.2006080936.

Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY et al. 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. 2004;28(1):1-30.

Frishberg Y, Ito N, Rinat C, Yamazaki Y, Feinstein S, Urakawa I et al. Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2007;22(2):235-42. doi:10.1359/jbmr.061105.

Fukumoto S, Ozono K, Michigami T, Minagawa M, Okazaki R, Sugimoto T et al. Pathogenesis and diagnostic criteria for rickets and osteomalacia-proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society. Journal of bone and mineral metabolism. 2015. doi:10.1007/s00774-015-0698-7.

Gibson MP, Zhu Q, Wang S, Liu Q, Liu Y, Wang X et al. The rescue of dentin matrix protein 1 (DMP1)-deficient tooth defects by the transgenic expression of dentin sialophosphoprotein (DSPP) indicates that DSPP is a downstream effector molecule of DMP1 in dentinogenesis. The Journal of biological chemistry. 2013;288(10):7204-14. doi:10.1074/jbc.M112.445775.

Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Molecular and cellular biology. 2007;27(9):3417-28. doi:10.1128/MCB.02249-06.

Goetz R, Nakada Y, Hu MC, Kurosu H, Wang L, Nakatani T et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(1):407-12. doi:10.1073/pnas.0902006107.

Goetz R, Ohnishi M, Kir S, Kurosu H, Wang L, Pastor J et al. Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. The Journal of biological chemistry. 2012;287(34):29134-46. doi:M112.342980 [pii] 10.1074/jbc.M112.342980 [doi].

Green CB, Takahashi JS, Bass J. The meter of metabolism. Cell. 2008;134(5):728-42. doi:10.1016/j.cell.2008.08.022.

Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119(19):2545-52. doi:10.1161/CIRCULATIONAHA.108.844506.

Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359(6):584-92. doi:359/6/584 [pii] 10.1056/NEJMoa0706130 [doi].

Han X, Xiao Z, Quarles LD. Membrane and integrative nuclear fibroblastic growth factor receptor (FGFR) regulation of FGF-23. The Journal of biological chemistry. 2015;290(33):20101. doi:10.1074/jbc.A114.609230.

Haussler MR, Whitfield GK, Kaneko I, Forster R, Saini R, Hsieh JC et al. The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. Rev Endocr Metab Disord. 2012;13(1):57-69. doi:10.1007/s11154-011-9199-8.

Hill KM, Martin BR, Wastney ME, McCabe GP, Moe SM, Weaver CM et al. Oral calcium carbonate affects calcium but not phosphorus balance in stage 3-4 chronic kidney disease. Kidney international. 2013;83(5):959-66. doi:10.1038/ki.2012.403.

Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 2003;17(13):1581-91. doi:10.1101/gad.1083503 [doi]


Hori M, Shimizu Y, Fukumoto S. Minireview: fibroblast growth factor 23 in phosphate homeostasis and bone metabolism. Endocrinology. 2011;152(1):4-10. doi:10.1210/en.2010-0800.

Hsu HJ, Wu MS. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci. 2009;337(2):116-22. doi:10.1097/MAJ.0b013e3181815498.

HYP-CONSORTIUM. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat Genet. 1995;11(2):130-6. doi:10.1038/ng1095-130 [doi].

Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. The Journal of clinical investigation. 2007;117(9):2684-91. doi:10.1172/JCI31330 [doi].

Ichikawa S, Sorenson AH, Austin AM, Mackenzie DS, Fritz TA, Moh A et al. Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression. Endocrinology. 2009;150(6):2543-50. doi:en.2008-0877 [pii] 10.1210/en.2008-0877 [doi].

Imel EA, DiMeglio LA, Hui SL, Carpenter TO, Econs MJ. Treatment of X-linked hypophosphatemia with calcitriol and phosphate increases circulating fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab. 2010;95(4):1846-50. doi:10.1210/jc.2009-1671.

Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2007;22(4):520-6. doi:10.1359/jbmr.070107.

Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011;96(11):3541-9. doi:jc.2011-1239 [pii] 10.1210/jc.2011-1239 [doi].

Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T et al. Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23. J Clin Endocrinol Metab. 2015;100(7):2565-73. doi:10.1210/jc.2015-1551.

Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N et al. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS letters. 2004;565(1-3):143-7. doi:10.1016/j.febslet.2004.03.090 [doi] S0014579304003990 [pii].

Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. Jama. 2011;305(23):2432-9. doi:10.1001/jama.2011.826.

Ito N, Findlay DM, Anderson PH, Bonewald LF, Atkins GJ. Extracellular phosphate modulates the effect of 1alpha,25-dihydroxy vitamin D3 (1,25D) on osteocyte like cells. J Steroid Biochem Mol Biol. 2013;136:183-6. doi:S0960-0760(12)00197-5 [pii] 10.1016/j.jsbmb.2012.09.029 [doi].

Ito N, Fukumoto S, Takeuchi Y, Takeda S, Suzuki H, Yamashita T et al. Effect of acute changes of serum phosphate on fibroblast growth factor (FGF)23 levels in humans. Journal of bone and mineral metabolism. 2007;25(6):419-22. doi:10.1007/s00774-007-0779-3 [doi].

Jean G, Terrat JC, Vanel T, Hurot JM, Lorriaux C, Mayor B et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2009;24(9):2792-6. doi:10.1093/ndt/gfp191.

Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003;348(17):1656-63. doi:10.1056/NEJMoa020881 [doi] 348/17/1656 [pii].

Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP et al. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. The Journal of biological chemistry. 2006;281(27):18370-7. doi:M602469200 [pii] 10.1074/jbc.M602469200 [doi].

Kawai M, Kinoshita S, Kimoto A, Hasegawa Y, Miyagawa K, Yamazaki M et al. FGF23 suppresses chondrocyte proliferation in the presence of soluble alpha-Klotho both in vitro and in vivo. The Journal of biological chemistry. 2013;288(4):2414-27. doi:10.1074/jbc.M112.410043.

Kawai M, Kinoshita S, Shimba S, Ozono K, Michigami T. Sympathetic activation induces skeletal Fgf23 expression in a circadian rhythm-dependent manner. The Journal of biological chemistry. 2014;289(3):1457-66. doi:10.1074/jbc.M113.500850.

Kawata T, Imanishi Y, Kobayashi K, Miki T, Arnold A, Inaba M et al. Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism. Journal of the American Society of Nephrology : JASN. 2007;18(10):2683-8. doi:10.1681/ASN.2006070783.

Kendrick J, Cheung AK, Kaufman JS, Greene T, Roberts WL, Smits G et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. Journal of the American Society of Nephrology : JASN. 2011;22(10):1913-22. doi:10.1681/ASN.2010121224.

Khan AM, Chirinos JA, Litt H, Yang W, Rosas SE. FGF-23 and the progression of coronary arterial calcification in patients new to dialysis. Clinical journal of the American Society of Nephrology : CJASN. 2012;7(12):2017-22. doi:10.2215/CJN.02160212.

Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ et al. FGF-21 as a novel metabolic regulator. The Journal of clinical investigation. 2005;115(6):1627-35. doi:10.1172/JCI23606 [doi].

Kirkpantur A, Balci M, Gurbuz OA, Afsar B, Canbakan B, Akdemir R et al. Serum fibroblast growth factor-23 (FGF-23) levels are independently associated with left ventricular mass and myocardial performance index in maintenance haemodialysis patients. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2011;26(4):1346-54. doi:10.1093/ndt/gfq539.

Kitaoka T, Namba N, Miura K, Kubota T, Ohata Y, Fujiwara M et al. Decrease in serum FGF23 levels after intravenous infusion of pamidronate in patients with osteogenesis imperfecta. Journal of bone and mineral metabolism. 2011;29(5):598-605. doi:10.1007/s00774-011-0262-z [doi].

Koh N, Fujimori T, Nishiguchi S, Tamori A, Shiomi S, Nakatani T et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochemical and biophysical research communications. 2001;280(4):1015-20. doi:10.1006/bbrc.2000.4226.

Kovesdy CP, Quarles LD. Fibroblast growth factor-23: what we know, what we don't know, and what we need to know. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2013a;28(9):2228-36. doi:10.1093/ndt/gft065.

Kovesdy CP, Quarles LD. The role of fibroblast growth factor-23 in cardiorenal syndrome. Nephron Clin Pract. 2013b;123(3-4):194-201. doi:10.1159/000353593.

Kubota T, Kitaoka T, Miura K, Fujiwara M, Ohata Y, Miyoshi Y et al. Serum fibroblast growth factor 23 is a useful marker to distinguish vitamin D-deficient rickets from hypophosphatemic rickets. Horm Res Paediatr. 2014;81(4):251-7. doi:10.1159/000357142.

Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45-51. doi:10.1038/36285 [doi].

Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP et al. Regulation of fibroblast growth factor-23 signaling by klotho. The Journal of biological chemistry. 2006;281(10):6120-3. doi:C500457200 [pii]

1074/jbc.C500457200 [doi].

Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney international. 2003;64(6):2272-9. doi:10.1046/j.1523-1755.2003.00328.x [doi].

Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. American journal of physiology Renal physiology. 2010;299(4):F882-9. doi:10.1152/ajprenal.00360.2010.

Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. American journal of human genetics. 2010;86(2):273-8. doi:10.1016/j.ajhg.2010.01.010.

Lindberg I, Pang HW, Stains JP, Clark D, Yang AJ, Bonewald L et al. FGF23 is endogenously phosphorylated in bone cells. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015;30(3):449-54. doi:10.1002/jbmr.2354.

Liu S, Tang W, Fang J, Ren J, Li H, Xiao Z et al. Novel Regulators of Fgf23 Expression and Mineralization in Hyp Bone. Mol Endocrinol. 2009;23(9):1505-18. doi:me.2009-0085 [pii] 10.1210/me.2009-0085 [doi].

Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. Journal of the American Society of Nephrology : JASN. 2006;17(5):1305-15. doi:ASN.2005111185 [pii] 10.1681/ASN.2005111185 [doi].

Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD. Pathogenic role of Fgf23 in Hyp mice. American journal of physiology Endocrinology and metabolism. 2006;291(1):E38-49. doi:00008.2006 [pii] 10.1152/ajpendo.00008.2006 [doi].

Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet. 2006;38(11):1248-50. doi:ng1868 [pii] 10.1038/ng1868 [doi].

Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. American journal of human genetics. 2010;86(2):267-72. doi:10.1016/j.ajhg.2010.01.006.

Mackenzie NC, Zhu D, Milne EM, van 't Hof R, Martin A, Darryl Quarles L et al. Altered bone development and an increase in FGF-23 expression in Enpp1(-/-) mice. PloS one. 2012;7(2):e32177. doi:10.1371/journal.pone.0032177.

Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge AM et al. Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP. Endocrinology. 2008;149(4):1757-72. doi:10.1210/en.2007-1205.

Martin A, David V, Li H, Dai B, Feng JQ, Quarles LD. Overexpression of the DMP1 C-terminal fragment stimulates FGF23 and exacerbates the hypophosphatemic rickets phenotype in Hyp mice. Mol Endocrinol. 2012;26(11):1883-95. doi:me.2012-1062 [pii] 10.1210/me.2012-1062 [doi].

Martin A, Liu S, David V, Li H, Karydis A, Feng JQ et al. Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2011;25(8):2551-62. doi:10.1096/fj.10-177816.

Michigami T. Extracellular phosphate as a signaling molecule. Contributions to nephrology. 2013;180:14-24. doi:10.1159/000346776.

Mirza MA, Larsson A, Melhus H, Lind L, Larsson TE. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis. 2009;207(2):546-51. doi:10.1016/j.atherosclerosis.2009.05.013.

Miyagawa K, Yamazaki M, Kawai M, Nishino J, Koshimizu T, Ohata Y et al. Dysregulated gene expression in the primary osteoblasts and osteocytes isolated from hypophosphatemic Hyp mice. PloS one. 2014;9(4):e93840. doi:10.1371/journal.pone.0093840.

Munoz Mendoza J, Isakova T, Ricardo AC, Xie H, Navaneethan SD, Anderson AH et al. Fibroblast growth factor 23 and Inflammation in CKD. Clinical journal of the American Society of Nephrology : CJASN. 2012;7(7):1155-62. doi:10.2215/CJN.13281211.

Nishida Y, Taketani Y, Yamanaka-Okumura H, Imamura F, Taniguchi A, Sato T et al. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney international. 2006;70(12):2141-7. doi:5002000 [pii] 10.1038/sj.ki.5002000 [doi].

Ohata Y, Arahori H, Namba N, Kitaoka T, Hirai H, Wada K et al. Circulating levels of soluble alpha-Klotho are markedly elevated in human umbilical cord blood. J Clin Endocrinol Metab. 2011;96(6):E943-7. doi:jc.2010-2357 [pii] 10.1210/jc.2010-2357 [doi].

Ohata Y, Yamazaki M, Kawai M, Tsugawa N, Tachikawa K, Koinuma T et al. Elevated fibroblast growth factor 23 exerts its effects on placenta and regulates vitamin D metabolism in pregnancy of Hyp mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014;29(7):1627-38. doi:10.1002/jbmr.2186.

Olauson H, Lindberg K, Amin R, Jia T, Wernerson A, Andersson G et al. Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism. Journal of the American Society of Nephrology : JASN. 2012;23(10):1641-51. doi:ASN.2012010048 [pii] 10.1681/ASN.2012010048 [doi].

Olauson H, Lindberg K, Amin R, Sato T, Jia T, Goetz R et al. Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet. 2013;9(12):e1003975. doi:10.1371/journal.pgen.1003975.

Parker BD, Schurgers LJ, Brandenburg VM, Christenson RH, Vermeer C, Ketteler M et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Annals of internal medicine. 2010;152(10):640-8. doi:10.7326/0003-4819-152-10-201005180-00004.

Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology. 2005;146(12):5358-64. doi:en.2005-0777 [pii] 10.1210/en.2005-0777 [doi].

Quinn SJ, Thomsen AR, Pang JL, Kantham L, Brauner-Osborne H, Pollak M et al. Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo. American journal of physiology Endocrinology and metabolism. 2013;304(3):E310-20. doi:10.1152/ajpendo.00460.2012.

Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S et al. Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2013;28(6):1378-85. doi:10.1002/jbmr.1850 [doi].

Razzaque MS. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis. Nature reviews Endocrinology. 2009;5(11):611-9. doi:10.1038/nrendo.2009.196.

Rhee Y, Bivi N, Farrow E, Lezcano V, Plotkin LI, White KE et al. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone. 2011;49(4):636-43. doi:S8756-3282(11)01066-0 [pii] 10.1016/j.bone.2011.06.025 [doi].

Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. The Journal of clinical investigation. 2003;112(5):683-92. doi:10.1172/JCI18399.

Rodriguez-Ortiz ME, Lopez I, Munoz-Castaneda JR, Martinez-Moreno JM, Ramirez AP, Pineda C et al. Calcium deficiency reduces circulating levels of FGF23. Journal of the American Society of Nephrology : JASN. 2012;23(7):1190-7. doi:10.1681/ASN.2011101006.

Rowe PS. The chicken or the egg: PHEX, FGF23 and SIBLINGs unscrambled. Cell biochemistry and function. 2012;30(5):355-75. doi:10.1002/cbf.2841.

Ruf N, Uhlenberg B, Terkeltaub R, Nurnberg P, Rutsch F. The mutational spectrum of ENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI). Human mutation. 2005;25(1):98. doi:10.1002/humu.9297.

Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W et al. Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. Nat Genet. 2003;34(4):379-81. doi:10.1038/ng1221.

Saji F, Shigematsu T, Sakaguchi T, Ohya M, Orita H, Maeda Y et al. Fibroblast growth factor 23 production in bone is directly regulated by 1{alpha},25-dihydroxyvitamin D, but not PTH. American journal of physiology Renal physiology. 2010;299(5):F1212-7. doi:10.1152/ajprenal.00169.2010.

Schouten BJ, Doogue MP, Soule SG, Hunt PJ. Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia. Annals of clinical biochemistry. 2009;46(Pt 2):167-9. doi:10.1258/acb.2008.008151.

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. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(11):6500-5. doi:10.1073/pnas.101545198 [doi] 101545198 [pii].

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(4):814-6. doi:10.1016/j.bone.2009.06.017.

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. American journal of human genetics. 2007;81(5):906-12. doi:10.1086/522240.

Sreenath T, Thyagarajan T, Hall B, Longenecker G, D'Souza R, Hong S et al. Dentin sialophosphoprotein knockout mouse teeth display widened predentin zone and develop defective dentin mineralization similar to human dentinogenesis imperfecta type III. The Journal of biological chemistry. 2003;278(27):24874-80. doi:10.1074/jbc.M303908200.

Stachowiak MK, Fang X, Myers JM, Dunham SM, Berezney R, Maher PA et al. Integrative nuclear FGFR1 signaling (INFS) as a part of a universal "feed-forward-and-gate" signaling module that controls cell growth and differentiation. Journal of cellular biochemistry. 2003;90(4):662-91. doi:10.1002/jcb.10606.

Stubbs JR, Liu S, Tang W, Zhou J, Wang Y, Yao X et al. Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. Journal of the American Society of Nephrology : JASN. 2007;18(7):2116-24. doi:ASN.2006121385 [pii] 10.1681/ASN.2006121385 [doi].

Tagliabracci VS, Engel JL, Wen J, Wiley SE, Worby CA, Kinch LN et al. Secreted kinase phosphorylates extracellular proteins that regulate biomineralization. Science. 2012;336(6085):1150-3. doi:science.1217817 [pii] 10.1126/science.1217817 [doi].

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. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(15):5520-5. doi:10.1073/pnas.1402218111.

Tagliabracci VS, Wiley SE, Guo X, Kinch LN, Durrant E, Wen J et al. A Single Kinase Generates the Majority of the Secreted Phosphoproteome. Cell. 2015;161(7):1619-32. doi:10.1016/j.cell.2015.05.028.

Takeuchi Y, Suzuki H, Ogura S, Imai R, Yamazaki Y, Yamashita T et al. Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia. J Clin Endocrinol Metab. 2004;89(8):3979-82. doi:10.1210/jc.2004-0406.

Takeyari S, Yamamoto T, Kinoshita Y, Fukumoto S, Glorieux FH, Michigami T et al. 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. 2014;67:56-62. doi:10.1016/j.bone.2014.06.026.

Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143(5):1741-7.

Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet. 2004;36(6):579-81. doi:10.1038/ng1358.

Tsuji K, Maeda T, Kawane T, Matsunuma A, Horiuchi N. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D3 synthesis in leptin-deficient mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2010;25(8):1711-23. doi:10.1002/jbmr.65.

Ubaidus S, Li M, Sultana S, de Freitas PH, Oda K, Maeda T et al. FGF23 is mainly synthesized by osteocytes in the regularly distributed osteocytic lacunar canalicular system established after physiological bone remodeling. J Electron Microsc (Tokyo). 2009;58(6):381-92. doi:dfp032 [pii] 10.1093/jmicro/dfp032 [doi].

Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444(7120):770-4. doi:nature05315 [pii] 10.1038/nature05315 [doi].

Wahl P, Wolf M. FGF23 in chronic kidney disease. Advances in experimental medicine and biology. 2012;728:107-25. doi:10.1007/978-1-4614-0887-1_8.

Wang X, Jung J, Liu Y, Yuan B, Lu Y, Feng JQ et al. The specific role of FAM20C in amelogenesis. Journal of dental research. 2013;92(11):995-9. doi:10.1177/0022034513504588.

Wang X, Wang J, Yuan B, Lu Y, Feng JQ, Qin C. Overexpression of Dmp1 fails to rescue the bone and dentin defects in Fam20C knockout mice. Connect Tissue Res. 2014;55(4):299-303. doi:10.3109/03008207.2014.923414.

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. 2012a;8(5):e1002708. doi:10.1371/journal.pgen.1002708 [doi] PGENETICS-D-11-02041 [pii].

Wang X, Wang S, Lu Y, Gibson MP, Liu Y, Yuan B et al. FAM20C plays an essential role in the formation of murine teeth. The Journal of biological chemistry. 2012b;287(43):35934-42. doi:10.1074/jbc.M112.386862.

White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S et al. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. American journal of human genetics. 2005;76(2):361-7. doi:S0002-9297(07)62588-9 [pii] 10.1086/427956 [doi].

White KE, Hum JM, Econs MJ. Hypophosphatemic rickets: revealing novel control points for phosphate homeostasis. Curr Osteoporos Rep. 2014;12(3):252-62. doi:10.1007/s11914-014-0223-2.

Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. Journal of the American Society of Nephrology : JASN. 2010;21(9):1427-35. doi:10.1681/ASN.2009121293.

Wolf M, Molnar MZ, Amaral AP, Czira ME, Rudas A, Ujszaszi A et al. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. Journal of the American Society of Nephrology : JASN. 2011;22(5):956-66. doi:10.1681/ASN.2010080894.

Xiao L, Esliger A, Hurley MM. Nuclear fibroblast growth factor 2 (FGF2) isoforms inhibit bone marrow stromal cell mineralization through FGF23/FGFR/MAPK in vitro. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2013;28(1):35-45. doi:10.1002/jbmr.1721.

Xiao L, Naganawa T, Lorenzo J, Carpenter TO, Coffin JD, Hurley MM. Nuclear isoforms of fibroblast growth factor 2 are novel inducers of hypophosphatemia via modulation of FGF23 and KLOTHO. The Journal of biological chemistry. 2010;285(4):2834-46. doi:10.1074/jbc.M109.030577.

Xiao Z, Huang J, Cao L, Liang Y, Han X, Quarles LD. Osteocyte-specific deletion of Fgfr1 suppresses FGF23. PloS one. 2014;9(8):e104154. doi:10.1371/journal.pone.0104154.

Yamazaki M, Kawai M, Miyagawa K, Ohata Y, Tachikawa K, Kinoshita S et al. Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation. Journal of bone and mineral metabolism. 2015;33(3):342-54. doi:10.1007/s00774-014-0598-2.

Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochemical and biophysical research communications. 2010;398(3):513-8. doi:S0006-291X(10)01250-7 [pii] 10.1016/j.bbrc.2010.06.110 [doi].

Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab. 2002;87(11):4957-60.

DOI: http://dx.doi.org/10.18103/mra.v2i5.381


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