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Iron and erythropoiesis: a dual relationship

  • Progress in Hematology
  • Seven wonders of erythropoiesis
  • Published:
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Abstract

Iron is essential for cell life and especially for erythropoiesis which is the major body consumer of iron for red cell production. The study of genetic disorders of iron metabolism, the identification of iron transporters and of the role of hepcidin as the key regulator of systemic iron homeostasis have greatly contributed to our understanding of iron handling by the erythroid marrow. Spontaneous and engineered animal models of iron disorders have help to add further insights to the issue. A still incompletely understood aspect remains the regulation that erythropoiesis exerts on iron.

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References

  1. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004;117:285–97.

    Article  CAS  PubMed  Google Scholar 

  2. Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet. 1999;21:396–9.

    Article  CAS  PubMed  Google Scholar 

  3. Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF. Molecular characterization of a case of atransferrinemia. Blood. 2000;96:4071–4.

    CAS  PubMed  Google Scholar 

  4. Trombini P, Coliva T, Nemeth E, Mariani R, Ganz T, Biondi A, et al. Effects of plasma transfusion on hepcidin production in human congenital hypotransferrinemia. Haematologica. 2007;92:1407–10.

    Article  CAS  PubMed  Google Scholar 

  5. Trenor CC 3rd, Campagna DR, Sellers VM, Andrews NC, Fleming MD. The molecular defect in hypotransferrinemic mice. Blood. 2000;96(3):1113–8.

    CAS  PubMed  Google Scholar 

  6. Bartnikas TB, Andrews NC, Fleming MD. Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice. Blood. doi:10.1182/blood-2010-05-287359.

  7. Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005;37(11):1264–9.

    Article  CAS  PubMed  Google Scholar 

  8. Ohgami RS, Campagna DR, Antiochos B, Wood EB, Sharp JJ, Barker JE, et al. nm1054: a spontaneous, recessive, hypochromic, microcytic anemia mutation in the mouse. Blood. 2005;106:3625–31.

    Article  CAS  PubMed  Google Scholar 

  9. Lim JE, Jin O, Bennett C, Morgan K, Wang F, Trenor CC 3rd, et al. A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice. Nat Genet. 2005;37:1270–3.

    Article  CAS  PubMed  Google Scholar 

  10. White RA, Boydston LA, Brookshier TR, McNulty SG, Nsumu NN, Brewer BP, et al. Iron metabolism mutant hbd mice have a deletion in Sec15l1, which has homology to a yeast gene for vesicle docking. Genomics. 2005;86:668–73.

    Article  CAS  PubMed  Google Scholar 

  11. Fleming MD, Trenor CC 3rd, Su MA, Foernzler D, Beier DR, Dietrich WF, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16:383–6.

    CAS  PubMed  Google Scholar 

  12. Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA. 1998;95:1148–53.

    Article  CAS  PubMed  Google Scholar 

  13. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482–8.

    Article  CAS  PubMed  Google Scholar 

  14. Iolascon A, Camaschella C, Pospisilova D, Piscopo C, Tchernia G, Beaumont C. Natural history of recessive inheritance of DMT1 mutations. J Pediatr. 2008;152:136–9.

    Article  CAS  PubMed  Google Scholar 

  15. Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest. 2005;115:1258–66.

    CAS  PubMed  Google Scholar 

  16. Kono S, Miyajima H. Molecular and pathological basis of aceruloplasminemia. Biol Res. 2006;39:15–23.

    Article  CAS  PubMed  Google Scholar 

  17. Kaneko Y, Miyajima H, Piperno A, Tomosugi N, Hayashi H, Morotomi N, et al. Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders. J Gastroenterol. 2010;45(11):1163–71.

    Article  CAS  PubMed  Google Scholar 

  18. Harris ZL, Durley AP, Man TK, Gitlin JD. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci USA. 1999;96:10812–7.

    Article  CAS  PubMed  Google Scholar 

  19. De Domenico I, Ward DM, di Patti MC, Jeong SY, David S, Musci G, et al. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J. 2007;26(12):2823–31.

    Article  PubMed  Google Scholar 

  20. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–23.

    Article  CAS  PubMed  Google Scholar 

  21. Fleming MD. The genetics of inherited sideroblastic anemias. Semin Hematol. 2002;39(4):270–81.

    Article  CAS  PubMed  Google Scholar 

  22. Yamamoto M, Nakajima O. Animal models for X-linked sideroblastic anemia. Int J Hematol. 2000;72:157–64.

    CAS  PubMed  Google Scholar 

  23. Nakajima O, Okano S, Harada H, Kusaka T, Gao X, Hosoya T, et al. Transgenic rescue of erythroid 5-aminolevulinate synthase-deficient mice results in the formation of ring sideroblasts and siderocytes. Genes Cells. 2006;11:685–700.

    Article  CAS  PubMed  Google Scholar 

  24. Guernsey DL, Jiang H, Campagna DR, Evans SC, Ferguson M, Kellogg MD, et al. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nat Genet. 2009;41(6):651–3.

    Article  CAS  PubMed  Google Scholar 

  25. Wingert RA, Galloway JL, Barut B, Foott H, Fraenkel P, Axe JL, et al. Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature. 2005;436(7053):1035–9.

    Article  CAS  PubMed  Google Scholar 

  26. Camaschella C, Campanella A, De Falco L, Boschetto L, Merlini R, Silvestri L, Levi S, Iolascon A. The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood. 2007;110(4):1353–8.

    Article  CAS  PubMed  Google Scholar 

  27. Ye H, Jeong SY, Ghosh MC, Kovtunovych G, Silvestri L, Ortillo D, Uchida N, Tisdale J, Camaschella C, Rouault TA. Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest. 2010;120(5):1749–61.

    Article  CAS  PubMed  Google Scholar 

  28. Bekri S, Kispal G, Lange H, Fitzsimons E, Tolmie J, Lill R, et al. Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. Blood. 2000;96:3256–64.

    CAS  PubMed  Google Scholar 

  29. Pondarre C, Campagna DR, Antiochos B, Sikorski L, Mulhern H, Fleming MD. Abcb7, the gene responsible for X-linked sideroblastic anemia with ataxia, is essential for hematopoiesis. Blood. 2007;109(8):3567–9.

    Article  CAS  PubMed  Google Scholar 

  30. Vulpe CD, Kuo YM, Murphy TL, Cowley L, Askwith C, Libina N, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet. 1999;21(2):195–9.

    Article  CAS  PubMed  Google Scholar 

  31. Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008;40(5):569–71.

    Article  CAS  PubMed  Google Scholar 

  32. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 2008;8(6):502–11.

    Article  CAS  PubMed  Google Scholar 

  33. Melis MA, Cau M, Congiu R, Sole G, Barella S, Cao A, et al. A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematologica. 2008;93(10):1473–9.

    Article  CAS  PubMed  Google Scholar 

  34. Guillem F, Lawson S, Kannengiesser C, Westerman M, Beaumont C, Grandchamp B. Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency. Blood. 2008;112(5):2089–91.

    Article  CAS  PubMed  Google Scholar 

  35. Silvestri L, Guillem F, Pagani A, Nai A, Oudin C, Silva M, et al. Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. Blood. 2009;113(22):5605–8.

    Article  CAS  PubMed  Google Scholar 

  36. De Falco L, Totaro F, Nai A, Pagani A, Girelli D, Silvestri L, et al. Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA). Hum Mutat. 2010;31(5):E1390–405.

    Article  PubMed  Google Scholar 

  37. Du X, She E, Gelbart T, Truksa J, Lee P, Xia Y, Khovananth K, Mudd S, Mann N, Moresco EM, Beutler E, Beutler B. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008;320:1088–92.

    Article  CAS  PubMed  Google Scholar 

  38. Folgueras AR, de Lara FM, Pendás AM, Garabaya C, Rodríguez F, Astudillo A, Bernal T, Cabanillas R, López-Otín C, Velasco G. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood. 2008;112:2539–45.

    Article  CAS  PubMed  Google Scholar 

  39. Gelvan D, Fibach E, Meyron-Holtz EG, Konijn AM. Ferritin uptake by human erythroid precursors is a regulated iron uptake pathway. Blood. 1996;88(8):3200–7.

    CAS  PubMed  Google Scholar 

  40. Leimberg JM, Prus E, Link G, Fibach E, Konijn AM. Iron-chelator complexes as iron sources for early developing human erythroid precursors. Transl Res. 2008;151(2):88–96.

    Article  CAS  PubMed  Google Scholar 

  41. Li L, Fang CJ, Ryan JC, Niemi EC, Lebrón JA, Björkman PJ, et al. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc Natl Acad Sci USA. 2010;107(8):3505–10.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang DL, Hughes RM, Ollivierre-Wilson H, Ghosh MC, Rouault TA. A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab. 2009;9(5):461–73.

    Article  CAS  PubMed  Google Scholar 

  43. Keel SB, Doty RT, Yang Z, Quigley JG, Chen J, Knoblaugh S, et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science. 2008;319:825–8.

    Article  CAS  PubMed  Google Scholar 

  44. Keel SB, Abkowitz JL. The microcytic red cell and the anemia of inflammation. N Engl J Med. 2009;361(19):1904–6.

    Article  CAS  PubMed  Google Scholar 

  45. Barton JC, Bertoli LF, Rothenberg BE. Peripheral blood erythrocyte parameters in hemochromatosis: evidence for increased erythrocyte hemoglobin content. J Lab Clin Med. 2000;135(1):96–10445.

    Article  CAS  PubMed  Google Scholar 

  46. Vujic Spasic M, Hentze M, Muckenthaler M. Extra-hepatic HFE functions may be responsible for iron oveload in the heart and alteration within the erythron. 2009 International poster 84, p 121.

  47. Roetto A, Di Cunto F, Pellegrino RM, Hirsch E, Azzolino O, Bondi A, et al. Comparison of 3 Tfr2-deficient murine models suggests distinct functions for Tfr2-alpha and Tfr2-beta isoforms in different tissues. Blood. 2010;115(16):3382–9.

    Article  CAS  PubMed  Google Scholar 

  48. Dallalio G, Law E, Means RT Jr. Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood. 2006;107(7):2702–4.

    Article  CAS  PubMed  Google Scholar 

  49. Finch C. Regulators of iron balance in humans. Blood. 1994;84(6):1697–702.

    CAS  PubMed  Google Scholar 

  50. Origa R, Galanello R, Ganz T, Giagu N, Maccioni L, Faa G, et al. Liver iron concentrations and urinary hepcidin in β-thalassemia. Haematologica. 2007;92:583–8.

    Article  CAS  PubMed  Google Scholar 

  51. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13:1096–101.

    Article  CAS  PubMed  Google Scholar 

  52. Tamary H, Shalev H, Perez-Avraham G, Zoldan M, Levi I, Swinkels DW, et al. Elevated growth differentiation factor 15 expression in patients with congenital dyserythropoietic anemia type I. Blood. 2008;112(13):5241–4.

    Article  CAS  PubMed  Google Scholar 

  53. Tanno T, Noel P, Miller JL. Growth differentiation factor 15 in erythroid health and disease. Curr Opin Hematol. 2010;17(3):184–90.

    CAS  PubMed  Google Scholar 

  54. Lakhal S, Schoedel J, Townsend AR, Pugh CW, Ratcliffe PJ, Mole DR. Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: new link between hypoxia signalling and iron homeostasis. J Biol Chem. doi:10.1074/jbc.M110.173096.

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Acknowledgments

This paper was partially supported by the European e-rare call 2009 and Cariplo Foundation Milano, Italy.

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  1. Division of Genetics and Cell Biology, Università Vita-Salute e IRCCS San Raffaele, Via Olgettina 60, 20132, Milan, Italy

    Clara Camaschella & Alessia Pagani

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  1. Clara Camaschella
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  2. Alessia Pagani
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Correspondence to Clara Camaschella.

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Camaschella, C., Pagani, A. Iron and erythropoiesis: a dual relationship. Int J Hematol 93, 21–26 (2011). https://doi.org/10.1007/s12185-010-0743-1

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  • DOI: https://doi.org/10.1007/s12185-010-0743-1

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