FGF23 Synthesis and Activity
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Purpose of Review
The phosphaturic hormone FGF23 is produced primarily in osteoblasts/osteocytes and is known to respond to increases in serum phosphate and 1,25(OH)2 vitamin D (1,25D). Novel regulators of FGF23 were recently identified and may help explain the pathophysiologies of several diseases. This review will focus on recent studies examining the synthesis and actions of FGF23.
The synthesis of FGF23 in response to 1,25D is similar to other steroid hormone targets, but the cellular responses to phosphate remain largely unknown. The activity of intracellular processing genes control FGF23 glycosylation and phosphorylation, providing critical functions in determining the serum levels of bioactive FGF23. The actions of FGF23 largely occur through its co-receptor αKlotho (KL) under normal circumstances, but FGF23 has KL-independent activity during situations of high concentrations.
Recent work regarding FGF23 synthesis and bioactivity, as well as considerations for diseases of altered phosphate balance, will be reviewed.
KeywordsFibroblast growth factor-23 FGF23 PTH Vitamin D Phosphate Klotho Rickets Osteomalacia GALNT3 FAM20C, PSC3 Furin
KEW receives royalties for licensing the FGF23 gene to Kyowa Hakko Kirin, Ltd.; the authors would like to acknowledge support by NIH grants DK112958, DK095784, and AR059278 (KEW), and T32-HL007910 (MLN).
Compliance with Ethical Standards
Conflict of Interest
Megan L. Noonan and Kenneth E. White each declare no potential conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as:•• Of major importance
- 1.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.CrossRefPubMedGoogle Scholar
- 4.•• 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. CrossRefPubMedPubMedCentralGoogle Scholar
- 6.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.CrossRefPubMedGoogle Scholar
- 7.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.CrossRefPubMedGoogle Scholar
- 12.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.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.
- 25.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.CrossRefPubMedGoogle Scholar
- 30.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.•• 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. CrossRefPubMedGoogle Scholar
- 42.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 47.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 53.•• 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. CrossRefPubMedPubMedCentralGoogle Scholar
- 54.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.CrossRefPubMedGoogle Scholar
- 59.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.CrossRefGoogle Scholar
- 71.•• 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. CrossRefPubMedPubMedCentralGoogle Scholar
- 72.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.