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Current Molecular Biology Reports

, Volume 5, Issue 1, pp 8–17 | Cite as

Regulation of Fibroblast Growth Factor 23 by Iron, EPO, and HIF

  • Jonathan A. Wheeler
  • Erica L. ClinkenbeardEmail author
Molecular Control of Phosphorus Homeostasis (B van der Eerden, Section Editor)
First Online:
  • 8 Downloads
Part of the following topical collections:
  1. Topical Collection on Molecular Control of Phosphorus Homeostasis

Abstract

Purpose of Review

Fibroblast growth factor-23 (FGF23) is the key hormone produced in bone critical for phosphate homeostasis. Elevated serum phosphorus and 1,25-dihydroxyvitamin D stimulates FGF23 production to promote renal phosphate excretion and decrease 1,25-dihydroxyvitamin D synthesis, thus completing the feedback loop and suppressing FGF23. Unexpectedly, studies of common and rare heritable disorders of phosphate handling identified links between iron and FGF23 demonstrating novel regulation outside the phosphate pathway.

Recent Findings

Iron deficiency combined with an FGF23 cleavage mutation was found to induce the autosomal dominant hypophosphatemic rickets phenotype. Physiological responses to iron deficiency, such as erythropoietin production as well as hypoxia inducible factor activation, have been indicated in regulating FGF23. Additionally, specific iron formulations, used to treat iron deficiency, alter post-translational processing thereby shifting FGF23 protein secretion.

Summary

Molecular and clinical studies revealed that iron deficiency, through several mechanisms, alters FGF23 at the transcriptional and post-translational level. This review will focus upon the novel discoveries elucidated between iron, its regulators, and their influence on FGF23 bioactivity.

Keywords

FGF-23 Iron Erythropoietin Phosphate Hypoxia-inducible factor 
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Notes

Funding Information

The authors would like to acknowledge NIH grants F32-AR065389 (ELC); the Comprehensive Training Program in Musculoskeletal Research Grant T32-AR065971 (JAW) and a Center for Translational Sciences Institutional Biomedical Research Grant (ELC).

Compliance with Ethical Standards

Conflict of Interest

Jonathan A. Wheeler and Erica L. Clinkenbeard 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.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    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(11):6500–5.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Weber TJ, Liu S, Indridason OS, Quarles LD. Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res. 2003;18(7):1227–34.PubMedGoogle Scholar
  3. 3.
    Yu X, White KE. FGF23 and disorders of phosphate homeostasis. Cytokine Growth Factor Rev. 2005;16(2):221–32.PubMedGoogle Scholar
  4. 4.
    Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y. A clinical and molecular genetic study of hypophosphatemic rickets in children. Pediatr Res. 2005;58(2):329–33.PubMedGoogle Scholar
  5. 5.
    Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44(4):601–7.PubMedGoogle Scholar
  6. 6.
    Yu X, White KE. Fibroblast growth factor 23 and its receptors. Ther Apher Dial. 2005;9(4):308–12.PubMedGoogle Scholar
  7. 7.
    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.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Kuro-o M. Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens. 2006;15(4):437–41.PubMedGoogle Scholar
  9. 9.
    Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem. 2006;281(10):6120–3.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Chen G, Liu Y, Goetz R, Fu L, Jayaraman S, Hu MC, et al. Alpha-klotho is a non- enzymatic molecular scaffold for FGF23 hormone signalling. Nature. 2018;553(7689):461–6.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Farrow EG, Summers LJ, Schiavi SC, McCormick JA, Ellison DH, White KE. Altered renal FGF23-mediated activity involving MAPK and Wnt: effects of the Hyp mutation. J Endocrinol. 2010;207(1):67–75.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Yamazaki Y, Tamada T, Kasai N, Urakawa I, Aono Y, Hasegawa H, et al. Anti-FGF23 neutralizing antibodies show the physiological role and structural features of FGF23. J Bone Miner Res. 2008;23(9):1509–18.PubMedGoogle Scholar
  13. 13.
    Saito H, Kusano K, Kinosaki M, Ito H, Hirata M, Segawa H, et al. Human fibroblast growth factor-23 mutants suppress Na+−dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production. J Biol Chem. 2003;278(4):2206–11.PubMedGoogle Scholar
  14. 14.
    Bacic D, Lehir M, Biber J, Kaissling B, Murer H, Wagner CA. The renal Na+/phosphate cotransporter NaPi-IIa is internalized via the receptor-mediated endocytic route in response to parathyroid hormone. Kidney Int. 2006;69(3):495–503.PubMedGoogle Scholar
  15. 15.
    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. J Am Soc Nephrol. 2006;17(5):1305–15.PubMedGoogle Scholar
  16. 16.
    Econs MJ, McEnery PT, Lennon F, Speer MC. Autosomal dominant hypophosphatemic rickets is linked to chromosome 12p13. J Clin Invest. 1997;100(11):2653–7.PubMedPubMedCentralGoogle Scholar
  17. 17.
    ADHR-Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000;26(3):345–348.Google Scholar
  18. 18.
    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.PubMedGoogle Scholar
  19. 19.
    Garringer HJ, Fisher C, Larsson TE, Davis SI, Koller DL, Cullen MJ, et al. The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis. J Clin Endocrinol Metab. 2006;91(10):4037–42.PubMedGoogle Scholar
  20. 20.
    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. J Bone Miner Res. 2007;22(2):235–42.PubMedGoogle Scholar
  21. 21.
    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(15):5520–5.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Alem AM, Sherrard DJ, Gillen DL, Weiss NS, Beresford SA, Heckbert SR, et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int. 2000;58(1):396–9.PubMedGoogle Scholar
  23. 23.
    Lefebvre P, Vekeman F, Sarokhan B, Enny C, Provenzano R, Cremieux PY. Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa. Curr Med Res Opin. 2006;22(10):1929–37.PubMedGoogle Scholar
  24. 24.
    Jamal SA. Bone mass measurements in men and women with chronic kidney disease. Curr Opin Nephrol Hypertens. 2010;19(4):343–8.PubMedGoogle Scholar
  25. 25.
    Rolvien T, Kornak U, Schinke T, Amling M, Oheim R. A novel FAM20C mutation causing hypophosphatemic osteomalacia with osteosclerosis (mild Raine syndrome) in an elderly man with spontaneous osteonecrosis of the knee. Osteoporos Int. 2018.Google Scholar
  26. 26.
    Min JH, Yang H, Ivan M, Gertler F, Kaelin WG Jr, Pavletich NP. Structure of an HIF- 1alpha -pVHL complex: hydroxyproline recognition in signaling. Science. 2002;296(5574):1886–9.PubMedGoogle Scholar
  27. 27.
    Hsu CY, McCulloch CE, Curhan GC. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the third National Health and nutrition examination survey. J Am Soc Nephrol. 2002;13(2):504–10.PubMedGoogle Scholar
  28. 28.
    Pak M, Lopez MA, Gabayan V, Ganz T, Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006;108(12):3730–5.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393–408.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Grabner A, Mazzaferro S, Cianciolo G, Krick S, Capelli I, Rotondi S, et al. Fibroblast growth factor 23: mineral metabolism and beyond. Contrib Nephrol. 2017;190:83–95.PubMedPubMedCentralGoogle Scholar
  31. 31.
    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(46):E1146–55.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Van Buren PN, Lewis JB, Dwyer JP, Greene T, Middleton J, Sika M, et al. The phosphate binder ferric citrate and mineral metabolism and inflammatory markers in maintenance Dialysis patients: results from Prespecified analyses of a randomized clinical trial. Am J Kidney Dis. 66(3):479–88.Google Scholar
  33. 33.
    Geissler C, Singh M. Iron, meat and health. Nutrients. 2011;3(3):283–316.PubMedPubMedCentralGoogle Scholar
  34. 34.
    McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, et al. An iron- regulated ferric reductase associated with the absorption of dietary iron. Science. 2001;291(5509):1755–9.PubMedGoogle Scholar
  35. 35.
    Andrews NC, Schmidt PJ. Iron homeostasis. Annu Rev Physiol. 2007;69:69–85.PubMedGoogle Scholar
  36. 36.
    Brannon PM, Taylor CL. Iron Supplementation during Pregnancy and Infancy: uncertainties and implications for research and policy. Nutrients. 2017;9(12).Google Scholar
  37. 37.
    Muller O, Krawinkel M. Malnutrition and health in developing countries. CMAJ. 2005;173(3):279–86.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Skalicky A, Meyers AF, Adams WG, Yang Z, Cook JT, Frank DA. Child food insecurity and iron deficiency anemia in low-income infants and toddlers in the United States. Matern Child Health J. 2006;10(2):177–85.PubMedGoogle Scholar
  39. 39.
    Diaz-Castro J, Lopez-Frias MR, Campos MS, Lopez-Frias M, Alferez MJ, Nestares T, et al. Severe nutritional iron-deficiency anaemia has a negative effect on some bone turnover biomarkers in rats. Eur J Nutr. 2012;51(2):241–7.PubMedGoogle Scholar
  40. 40.
    Cartwright GE, Lauritsen MA, Humphreys S, Jones PJ, Merrill IM, Wintrobe MM. The Anemia associated with chronic infection. Science. 1946;103(2664):72–3.PubMedGoogle Scholar
  41. 41.
    Cartwright GE, Lauritsen MA, Jones PJ, Merrill IM, Wintrobe MM. The Anemia of infection. I. Hypoferremia, hypercupremia, and alterations in porphyrin metabolism in patients. J Clin Invest. 1946;25(1):65–80.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Qamar K, Saboor M, Qudsia F, Khosa SM. Moinuddin, Usman M. Malabsorption of iron as a cause of iron deficiency anemia in postmenopausal women. Pak J Med Sci. 2015;31(2):304–8.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Filmann N, Rey J, Schneeweiss S, Ardizzone S, Bager P, Bergamaschi G, et al. Prevalence of anemia in inflammatory bowel diseases in european countries: a systematic review and individual patient data meta-analysis. Inflamm Bowel Dis. 2014;20(5):936–45.PubMedGoogle Scholar
  44. 44.
    Gotloib L, Silverberg D, Fudin R, Shostak A. Iron deficiency is a common cause of anemia in chronic kidney disease and can often be corrected with intravenous iron. J Nephrol. 2006;19(2):161–7.PubMedGoogle Scholar
  45. 45.
    Lankhorst CE, Wish JB. Anemia in renal disease: diagnosis and management. Blood Rev. 2010;24(1):39–47.PubMedGoogle Scholar
  46. 46.
    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.PubMedGoogle Scholar
  47. 47.
    Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. 2007;22(4):520–6.PubMedGoogle Scholar
  48. 48.
    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;96:3541–9.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Vieth JT, Lane DR. Anemia. Emerg Med Clin North Am. 2014;32(3):613–28.PubMedGoogle Scholar
  50. 50.
    Bryan LJ, Zakai NA. Why is my patient anemic? Hematol Oncol Clin North Am. 2012;26(2):205–30 vii.PubMedGoogle Scholar
  51. 51.
    Rabadi S, Udo I, Leaf DE, Waikar SS, Christov M. Acute blood loss stimulates fibroblast growth factor 23 production. Am J Physiol Renal Physiol. 2018;314(1):F132–F9.PubMedGoogle Scholar
  52. 52.
    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(8):1793–803.PubMedGoogle Scholar
  53. 53.
    Lewerin C, Ljunggren O, Nilsson-Ehle H, Karlsson MK, Herlitz H, Lorentzon M, et al. Low serum iron is associated with high serum intact FGF23 in elderly men: the Swedish MrOS study. Bone. 2017;98:1–8.PubMedGoogle Scholar
  54. 54.
    Erlitzki R, Long JC, Theil EC. Multiple, conserved iron-responsive elements in the 3′- untranslated region of transferrin receptor mRNA enhance binding of iron regulatory protein 2. J Biol Chem. 2002;277(45):42579–87.PubMedGoogle Scholar
  55. 55.
    Thomson AM, Rogers JT, Leedman PJ. Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation. Int J Biochem Cell Biol. 1999;31(10):1139–52.PubMedGoogle Scholar
  56. 56.
    Piccinelli P, Samuelsson T. Evolution of the iron-responsive element. RNA. 2007;13(7):952–66.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Sanchez M, Galy B, Schwanhaeusser B, Blake J, Bahr-Ivacevic T, Benes V, et al. Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins. Blood. 2011;118(22):e168–79.PubMedGoogle Scholar
  58. 58.
    Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A. 1993;90(9):4304–8.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007;117(7):1926–32.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468–72.PubMedGoogle Scholar
  61. 61.
    Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler V, Kondo K, et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2002;99(21):13459–64.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFalpha targeted for VHL- mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–8.PubMedGoogle Scholar
  63. 63.
    Schodel J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR. High- resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood. 2011;117(23):e207–17.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Bailey PSJ, Nathan JA. Metabolic Regulation of Hypoxia-Inducible Transcription Factors: The Role of Small Molecule Metabolites and Iron. Biomedicines. 2018;6(2).Google Scholar
  65. 65.
    Bianchi L, Tacchini L, Cairo G. HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. Nucleic Acids Res. 1999;27(21):4223–7.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Weinberg ED. Iron withholding: a defense against infection and neoplasia. Physiol Rev. 1984;64(1):65–102.PubMedGoogle Scholar
  67. 67.
    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. 2016;89(1):135–46.PubMedPubMedCentralGoogle Scholar
  68. 68.
    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.PubMedPubMedCentralGoogle Scholar
  69. 69.
    •• Onal M, Carlson AH, Thostenson JD, Benkusky NA, Meyer MB, Lee SM, 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(1):32–47 This study demonstrated the regulation of FGF23 by a distal upstream enhancer. PubMedGoogle Scholar
  70. 70.
    Bruning U, Fitzpatrick SF, Frank T, Birtwistle M, Taylor CT, Cheong A. NFkappaB and HIF display synergistic behaviour during hypoxic inflammation. Cell Mol Life Sci. 69(8):1319–29.Google Scholar
  71. 71.
    Jacobson LO, Goldwasser E, Fried W, Plzak L. Role of the kidney in erythropoiesis. Nature. 1957;179(4560):633–4.PubMedGoogle Scholar
  72. 72.
    Franke K, Gassmann M, Wielockx B. Erythrocytosis: the HIF pathway in control. Blood. 2013;122(7):1122–8.PubMedGoogle Scholar
  73. 73.
    Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A. CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. J Biol Chem. 2000;275(38):29338–47.PubMedGoogle Scholar
  74. 74.
    Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46(7):678–84.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Arezes J, Foy N, McHugh K, Sawant A, Quinkert D, Terraube V, et al. Erythroferrone inhibits the induction of hepcidin by BMP6. Blood. 2018;132:1473–7.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Daryadel A, Bettoni C, Haider T, Imenez Silva PH, Schnitzbauer U, Pastor-Arroyo EM, et al. Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men. Pflugers Arch. 2018;470:1569–82.PubMedGoogle Scholar
  77. 77.
    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.Google Scholar
  78. 78.
    Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a potential new treatment for Anemia in patients with CKD. Am J Kidney Dis. 2017;69(6):815–26.PubMedGoogle Scholar
  79. 79.
    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(10):e0186979.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Toro L, Barrientos V, Leon P, Rojas M, Gonzalez M, Gonzalez-Ibanez A, et al. Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury. Kidney Int. 2018;93(5):1131–41.PubMedGoogle Scholar
  81. 81.
    Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631–4.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Hinata A, Iijima M, Nakano Y, Sakamoto T, Tomita M. Chemical characterization of rabbit alpha 2-macroglobulin. Chem Pharm Bull (Tokyo). 1987;35(1):271–6.Google Scholar
  83. 83.
    Landau D, London L, Bandach I, Segev Y. The hypoxia inducible factor/erythropoietin (EPO)/EPO receptor pathway is disturbed in a rat model of chronic kidney disease related anemia. PLoS One. 2018;13(5):e0196684.PubMedPubMedCentralGoogle Scholar
  84. 84.
    •• 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(11):e427–e30 This study demonstrated EPO stimulation of FGF23 independent of HIF that occurs in both osteoblast/osteocytes as well as hematopoietic lineage cells. PubMedPubMedCentralGoogle Scholar
  85. 85.
    Singbrant S, Russell MR, Jovic T, Liddicoat B, Izon DJ, Purton LE, et al. Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment. Blood. 2011;117(21):5631–42.PubMedGoogle Scholar
  86. 86.
    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(2):361–9.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Duval F, Mokrani MC, Monreal J, Weiss T, Fattah S, Hamel B, et al. Interaction between the serotonergic system and HPA and HPT axes in patients with major depression: implications for pathogenesis of suicidal behavior. Dialogues Clin Neurosci. 2002;4(4):417.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Okada M, Imamura K, Fuchigami T, Omae T, Iida M, Nanishi F, et al. 2 cases of nonspecific multiple ulcers of the small intestine associated with osteomalacia caused by long- term intravenous administration of saccharated ferric oxide. Nihon Naika Gakkai zasshi The Journal of the Japanese Society of Internal Medicine. 1982;71(11):1566–72.PubMedGoogle Scholar
  89. 89.
    Auerbach M, Macdougall IC. Oral Iron therapy: after three centuries, it is time for a change. Am J Kidney Dis. 2016;68(5):665–6.PubMedGoogle Scholar
  90. 90.
    Geisser P, Burckhardt S. The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011;3(1):12–33.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Bishay RH, Ganda K, Seibel MJ. Long-term iron polymaltose infusions associated with hypophosphataemic osteomalacia: a report of two cases and review of the literature. Ther Adv Endocrinol Metab. 2017;8(1–2):14–9.PubMedGoogle Scholar
  92. 92.
    Gilmartin CE, Hoang T, Cutts BA, Leung L. Retrospective cohort study comparing the adverse reactions and efficacy of intravenous iron polymaltose with ferric carboxymaltose for iron deficiency anemia. Int J Gynaecol Obstet. 2018;141(3):315–20.PubMedGoogle Scholar
  93. 93.
    Urbina T, Belkhir R, Rossi G, Carbonnel F, Pavy S, Collins M, et al. Iron supplementation-induced Phosphaturic Osteomalacia: FGF23 is the culprit. J Bone Miner Res. 2018;33(3):540–2.PubMedGoogle Scholar
  94. 94.
    Bartko J, Roschger P, Zandieh S, Brehm A, Zwerina J, Klaushofer K. Hypophosphatemia, severe bone pain, gait disturbance, and fatigue fractures after Iron substitution in inflammatory bowel disease: a case report. J Bone Miner Res. 2018;33(3):534–9.PubMedGoogle Scholar
  95. 95.
    Klein K, Asaad S, Econs M, Rubin JE. Severe FGF23-based hypophosphataemic osteomalacia due to ferric carboxymaltose administration. BMJ Case Rep. 2018;2018.Google Scholar
  96. 96.
    Tulewicz-Marti E, Moniuszko A, Rydzewska G. Management of anemia in inflammatory bowel disease: a challenge in everyday clinical practice. Przeglad gastroenterologiczny. 2017;12(4):239–43.PubMedPubMedCentralGoogle Scholar
  97. 97.
    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.PubMedPubMedCentralGoogle Scholar
  98. 98.
    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.PubMedPubMedCentralGoogle Scholar
  99. 99.
    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. J Am Soc Nephrol. 2011;22(5):956–66.PubMedPubMedCentralGoogle Scholar
  100. 100.
    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.PubMedGoogle Scholar
  101. 101.
    Fukao W, Hasuike Y, Yamakawa T, Toyoda K, Aichi M, Masachika S, et al. Oral versus intravenous Iron supplementation for the treatment of Iron deficiency Anemia in patients on maintenance hemodialysis-effect on fibroblast growth Factor-23 metabolism. J Renal Nutr. 2018;28(4):270–7.Google Scholar
  102. 102.
    Liabeuf S, Ryckelynck JP, El Esper N, Urena P, Combe C, Dussol B, et al. Randomized clinical trial of Sevelamer carbonate on serum klotho and fibroblast growth factor 23 in CKD. Clin J Am Soc Nephrol. 2017;12(12):1930–40.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Koiwa F, Yokoyama K, Fukagawa M, Terao A, Akizawa T. Efficacy and safety of sucroferric oxyhydroxide compared with sevelamer hydrochloride in Japanese haemodialysis patients with hyperphosphataemia: a randomized, open-label, multicentre, 12-week phase III study. Nephrology (Carlton). 2017;22(4):293–300.Google Scholar
  104. 104.
    Covic AC, Floege J, Ketteler M, Sprague SM, Lisk L, Rakov V, et al. Iron-related parameters in dialysis patients treated with sucroferric oxyhydroxide. Nephrol Dial Transplant. 2017;32(8):1330–8.PubMedGoogle Scholar
  105. 105.
    Yang WC, Yang CS, Hou CC, Wu TH, Young EW, Hsu CH. An open-label, crossover study of a new phosphate-binding agent in haemodialysis patients: ferric citrate. Nephrol Dial Transplant. 2002;17(2):265–70.PubMedGoogle Scholar
  106. 106.
    Lee CT, Wu IW, Chiang SS, Peng YS, Shu KH, Wu MJ, et al. Effect of oral ferric citrate on serum phosphorus in hemodialysis patients: multicenter, randomized, double-blind, placebo- controlled study. J Nephrol. 2015;28(1):105–13.PubMedGoogle Scholar
  107. 107.
    Maruyama N, Otsuki T, Yoshida Y, Nagura C, Kitai M, Shibahara N, et al. Ferric citrate decreases fibroblast growth factor 23 and improves erythropoietin responsiveness in hemodialysis patients. Am J Nephrol. 2018;47(6):406–14.PubMedGoogle Scholar
  108. 108.
    Iguchi A, Yamamoto S, Yamazaki M, Tasaki K, Suzuki Y, Kazama JJ, et al. Effect of ferric citrate hydrate on FGF23 and PTH levels in patients with non-dialysis-dependent chronic kidney disease with normophosphatemia and iron deficiency. Clin Exp Nephrol. 2018;22(4):789–96.PubMedGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisUSA
  2. 2.Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisUSA

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