Erythroferron: Modern Concepts of Its Role in Iron Metabolism Regulation

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.

• Valerii Timofeevich Sakhin Military Clinical Hospital No. 1586 under the Ministry of Defense of Russia, 4 Mashtakova str., Podol’sk, Moscow Oblast, Russian Federation, 142110 ; ФГКУ «1586 Военный клинический госпиталь» МО РФ, ул. Маштакова, д. 4, Подольск, Московская область, Российская Федерация, 142110
• N.V. Kremneva Military Clinical Hospital No. 1586 under the Ministry of Defense of Russia, 4 Mashtakova str., Podol’sk, Moscow Oblast, Russian Federation, 142110 ; ФГКУ «1586 Военный клинический госпиталь» МО РФ, ул. Маштакова, д. 4, Подольск, Московская область, Российская Федерация, 142110
• A.V. Gordienko SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044 ; ФГБВОУ ВПО «Военно-медицинская академия им. С.М. Кирова» МО РФ, ул. Академика Лебедева, д. 6, Санкт-Петербург, Российская Федерация, 194044
• O.A. Rukavitsyn NN Burdenko Principal Military Clinical Hospital under the Ministry of Defense of Russia, 3 Gospital’naya pl., Moscow, Russian Federation, 105229 ; ФГКУ «Главный военный клинический госпиталь им. Н.Н. Бурденко» МО РФ, Госпитальная пл., д. 3, Москва, Российская Федерация, 105229

1. Гематология: национальное руководство. Под ред. О.А. Рукавицына. М.: ГЭОТАР-Медиа, 2015. С. 143–9.
2. [Rukavitsyn OA, ed. Gematologiya: natsional’noe rukovodstvo. (Hematology: national guidelines.) Moscow: GEOTAR-Media Publ.; 2015. pp. 143–9. (In Russ)]
3. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823(9):1434–43. doi: 10.1016/j.bbamcr.2012.01.014. DOI: https://doi.org/10.1016/j.bbamcr.2012.01.014
4. 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. DOI: https://doi.org/10.1172/JCI200215686
5. 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. DOI: https://doi.org/10.1172/JCI31370
6. 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. DOI: https://doi.org/10.1182/blood-2007-08-106195
7. 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. DOI: https://doi.org/10.1172/JCI63924
8. 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. DOI: https://doi.org/10.1182/blood-2006-06-028787
9. 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. DOI: https://doi.org/10.33549/physiolres.930841
10. 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. DOI: https://doi.org/10.1038/nm1629
11. 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. DOI: https://doi.org/10.1182/blood-2008-12-195503
12. 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. DOI: https://doi.org/10.1016/j.cytogfr.2013.05.003
13. 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. DOI: https://doi.org/10.1016/j.ydbio.2012.10.007
14. 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. DOI: https://doi.org/10.1111/j.1365-2141.2012.09104.x
15. 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. DOI: https://doi.org/10.3324/haematol.2012.069807
16. 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. DOI: https://doi.org/10.1182/blood-2008-06-165738
17. 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. DOI: https://doi.org/10.1182/blood-2014-01-548305
18. 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. DOI: https://doi.org/10.1111/j.1537-2995.2010.02601.x
19. 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. DOI: https://doi.org/10.1111/j.1365-2141.2009.07961.x
20. 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. DOI: https://doi.org/10.1111/j.1600-0609.2011.01631.x
21. 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. DOI: https://doi.org/10.1038/ng.2996
22. 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. DOI: https://doi.org/10.1182/blood-2011-08-377424
23. 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. DOI: https://doi.org/10.1002/hep.26550
24. 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. DOI: https://doi.org/10.1016/S0140-6736(79)92175-5
25. 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. DOI: https://doi.org/10.1182/blood-2004-12-4844
26. 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. DOI: https://doi.org/10.1182/blood.V96.10.3624.h8003624_3624_3629
27. 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.
28. 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. DOI: https://doi.org/10.3324/haematol.10842
29. 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. DOI: https://doi.org/10.1182/blood-2012-01-401885
30. 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. DOI: https://doi.org/10.1172/JCI66969
31. 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. DOI: https://doi.org/10.1182/blood-2012-09-453977
32. 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. DOI: https://doi.org/10.1182/blood-2010-05-286260