Erythroferron: Modern Concepts of Its Role in Iron Metabolism Regulation

REVIEWS , ,

VT Sakhin1, NV Kremneva1, AV Gordienko2, OA Rukavitsyn3

1 Military Clinical Hospital No. 1586 under the Ministry of Defense of Russia, 4 Mashtakova str., Podol’sk, Moscow Oblast, Russian Federation, 142110

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3 NN Burdenko Principal Military Clinical Hospital under the Ministry of Defense of Russia, 3 Gospital’naya pl., Moscow, Russian Federation, 105229

For correspondence: Valerii Timofeevich Sakhin, PhD, 4 Mashtakova str., Podol’sk, Moscow Oblast, Russian Federation, 142110; Tel: +7(916)314-31-11; e-mail: SahinVT@yandex.ru

For citation: Sakhin VT, Kremneva NV, Gordienko AV, Rukavitsyn OA. Erythroferron: Modern Concepts of Its Role in Iron Metabolism Regulation. Clinical oncohematology. 2017;10(1):25–8 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-25-28

ABSTRACT

The article presents the results of experimental and clinical studies evaluating the importance of supposed erythroid regulators of hepcidin levels and mechanism of their action. It demonstrates that the role of growth differentiation factor 15 and twisted gastrulation protein homolog 1 in regulation of hepcidin levels in humans has not been confirmed yet. The data confirming the importance of erythroferron in the pathogenesis of anemia related to blood loss, hemolysis, and hereditary anemias with ineffective erythropoiesis are presented. The studies demonstrated that erythroferron plays the greatest role in the regulation of hepcidin levels in pathological conditions and at stress and does not play a leading role in erythropoiesis under normal conditions. Erythroferron suppresses the hepcidin synthesis by affecting the liver cells directly through an unknown receptor cellular pathway.

Keywords: anemia of chronic disease, hepcidin, erythroferron.

Received: September 14, 2016

Accepted: November 13, 2016

Read in PDF (RUS)pdficon

REFERENCES

  1. Гематология: национальное руководство. Под ред. О.А. Рукавицына. М.: ГЭОТАР-Медиа, 2015. С. 143–9.
    [Rukavitsyn OA, ed. Gematologiya: natsional’noe rukovodstvo. (Hematology: national guidelines.) Moscow: GEOTAR-Media Publ.; 2015. pp. 143–9. (In Russ)]
  2. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823(9):1434–43. doi: 10.1016/j.bbamcr.2012.01.014.
  3. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidinis regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110(7):1037–44. doi: 10.1172/jci0215686.
  4. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007;117(7):1926–32. doi: 10.1172/jci31370.
  5. Pinto JP, Ribeiro S, Pontes H, et al. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBP alpha. Blood. 2008;111(12):5727–33. doi: 10.1182/blood-2007-08-106195.
  6. Liu Q, Davidoff O, Niss K, et al. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest. 2012;122(12):4635–44. doi: 10.1172/jci63924.
  7. Pak M, Lopez MA, Gabayan V, et al. Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006;108(12):3730–5. doi: 10.1182/blood-2006-06-028787.
  8. Vokurka M, Krijt J, Sulc K, Necas E. Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Phys Res. 2006;55(6):667–74.
  9. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13(9):1096–101. doi: 10.1038/nm1629.
  10. Tanno T, Porayette P, Sripichai O, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114(1):181–6. doi: 10.1182/blood-2008-12-195503.
  11. Unsicker K, Spittau B, Krieglstein K. The multiple facets of the TGF-b family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1. Cyt Growth Factor Rev. 2013;24(4):373–84. doi: 10.1016/j.cytogfr.2013.05.003.
  12. Forsman CL, Ng BC, Heinze RK, et al. BMP-binding protein twisted gastrulation is required in mammary gland epithelium for normal ductal elongation and myoepithelial compartmentalization. Devel Biol. 2013;373(1):95–106. doi: 10.1016/j.ydbio.2012.10.007.
  13. Frazer DM, Wilkins SJ, Darshan D, et al. Stimulated erythropoiesis with secondary iron loading leads to a decrease in hepcidin despite an increase in bone morphogenetic protein 6 expression. Br J Haematol. 2012;157(5):615–26. doi: 10.1111/j.1365-2141.2012.09104.x.
  14. Casanovas G, Spasic MV, Casu C, et al. The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice. Haematologica. 2013;98(3):444–7. doi: 10.3324/haematol.2012.069807.
  15. Tamary H, Shalev H, Perez-Avraham G, et al. Elevated growth differentiation factor 15 expression in patients with congenital dyserythropoietic anemia type I. Blood. 2008;112(13):5241–4. doi: 10.1182/blood-2008-06-165738.
  16. An X, Schulz VP, Li J, et al. Global transcriptome analyses of human and murine terminal erythroid differentiation. Blood. 2014;123(22):3466–77. doi: 10.1182/blood-2014-01-548305.
  17. Tanno T, Rabel A, Lee YT, et al. Expression of growth differentiation factor 15 is not elevated in individuals with iron deficiency secondary to volunteer blood donation. Transfusion. 2010;50(7):1532–5. doi: 10.1111/j.1537-2995.2010.02601.x.
  18. Theurl I, Finkenstedt A, Schroll A, et al. Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia. Br J Haematol. 2010;148(3):449–55. doi: 10.1111/j.1365-2141.2009.07961.x.
  19. Waalen J, von Lohneysen K, Lee P, et al. Erythropoietin, GDF15, IL6, hepcidin and testosterone levels in a large cohort of elderly individuals with anaemia of known and unknown cause. Eur J Haematol. 2011;87(2):107–16. doi: 10.1111/j.1600-0609.2011.01631.x.
  20. Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46(7):678–84. doi: 10.1038/ng.2996.
  21. Merryweather-Clarke AT, Atzberger A, Soneji S, et al. Global gene expression analysis of human erythroid progenitors. Blood. 2011;118(26):e96–108. doi: 10.1182/blood-2010-07-290825.
  22. Diaz V, Gammella E, Recalcati S, et al. Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice. Hepatology. 2013;58(6):2122–32. doi: 10.1002/hep.26550.
  23. Pippard MJ, Warner GT, Callender ST, Weatherall DJ. Iron absorption and loading in b-thalassaemia intermedia. Lancet. 1979;314(8147):819–21. doi: 10.1016/s0140-6736(79)92175-5.
  24. Papanikolaou G, Tzilianos M, Christakis JI, et al. Hepcidin in iron overload disorders. Blood. 2005;105(10):4103–5. doi: 10.1182/blood-2004-12-4844.
  25. Centis F, Tabellini L, Lucarelli G, et al. The importance of erythroid expansion in determining the extent of apoptosis in erythroid precursors in patients with b-thalassemia major. Blood. 2000;96(10):3624–9.
  26. Kattamis A, Papassotiriou I, Palaiologou D, et al. The effects of erythropoetic activity and iron burden on hepcidin expression in patients with thalassemia major. Haematologica. 2006;91(6):809–12.
  27. Origa R, Galanello R, Ganz T, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. 2007;92(5):583–8. doi: 10.3324/haematol.10842.
  28. Nai A, Pagani A, Mandelli G, et al. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia. Blood. 2012;119(21):5021–9. doi: 10.1182/blood-2012-01-401885.
  29. Guo S, Casu C, Gardenghi S, et al. Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice. J Clin Invest. 2013;123(4):1531–41. doi: 10.1172/JCI66969.
  30. Schmidt PJ, Toudjarska I, Sendamarai AK, et al. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe–/– mice and ameliorates anemia and iron overload in murine beta-thalassemia intermedia. Blood. 2013;121(7):1200–8. doi: 10.1182/blood-2012-09-453977.
  31. Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood. 2010;116(23):4754–61. doi: 10.1182/blood-2010-05-286260.