An update on iron homeostasis: Make new friends, but keep the old

American Journal of the Medical Sciences

Volumn 346, Issue 5, 2013, Pages 413-419

  Roy, Cindy N ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Bone morphogenetic protein; Hepcidin; Hereditary hemochromatosis; Iron homeostasis

Indexed keywords

ACTIVIN RECEPTOR LIKE KINASE 1; ACTIVIN RECEPTOR LIKE KINASE 4; BONE MORPHOGENETIC PROTEIN 6; FERROPORTIN; HEMOJUVELIN; HEPCIDIN; IRON CHELATING AGENT; MITOGEN ACTIVATED PROTEIN KINASE; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; NEOGENIN; TRANSFERRIN RECEPTOR; TRANSFERRIN RECEPTOR 2; UNCLASSIFIED DRUG;

ANEMIA; CONFERENCE PAPER; GENE MUTATION; GENE PRODUCT; HEMOCHROMATOSIS; HOMEOSTASIS; HUMAN; INTRACELLULAR SIGNALING; IRON CHELATION; IRON HOMEOSTASIS; IRON OVERLOAD; NONHUMAN; PHLEBOTOMY;

EID: 84887252574     PISSN: 00029629     EISSN: 15382990     Source Type: Journal    
DOI: 10.1097/MAJ.0000000000000190     Document Type: Conference Paper

References (106)

1. Gunshin H, Fujiwara Y, Custodio AO, et al. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 2005;115:1258-66.
2. Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997;388:482-8.
3. Fleming MD, Trenor CC III, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 1997;16:383-6.
4. Rajagopal A, Rao AU, Amigo J, et al. Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins. Nature 2008;453:1127-31.
5. White C, Yuan X, Schmidt PJ, et al. HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab 2013;17:261-70.
6. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/ Slc40a1 is essential for iron homeostasis. Cell Metab 2005;1:191-200.
7. McKie AT, Marciani P, Rolfs A, et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000;5:299-309.
8. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000;275: 19906-12.
9. Krause A, Neitz S, Magert HJ, et al. LEAP-1, a novel highly disulfidebonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000; 480:147-50.
10. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276: 7806-10.
11. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090-3.
12. Qiao B, Sugianto P, Fung E, et al. Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab 2012;15:918-24.
13. Ross SL, Tran L, Winters A, et al. Molecular mechanism of hepcidin- mediated ferroportin internalization requires ferroportin lysines, not tyrosines or JAK-STAT. Cell Metab 2012;15:905-17.
14. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001; 276:7811-9.
15. Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003;101:2461-3.
16. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:1271-6.
17. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002;110:1037-44.
18. Ganz T, Olbina G, Girelli D, et al. Immunoassay for human serum hepcidin. Blood 2008;112:4292-7.
19. Hentze MW, Muckenthaler MU, Galy B, et al. Two to tango: regulation of Mammalian iron metabolism. Cell 2010;142:24-38.
20. Merryweather-Clarke AT, Cadet E, Bomford A, et al. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet 2003;12:2241-7.
21. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 2003;33:21-2.
22. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004;36:77-82.
23. Nemeth E, Roetto A, Garozzo G, et al. Hepcidin is decreased in TFR2 hemochromatosis. Blood 2005;105:1803-6.
24. Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 2003;361:669-73.
25. Piperno A, Girelli D, Nemeth E, et al. Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Blood 2007;110: 4096-100.
26. Montosi G, Donovan A, Totaro A, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 2001;108:619-23.
27. Njajou OT, Vaessen N, Joosse M, et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 2001;28:213-4.
28. Gordeuk VR, Caleffi A, Corradini E, et al. Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells Mol Dis 2003;31:299-304.
29. Zoller H, McFarlane I, Theurl I, et al. Primary iron overload with inappropriate hepcidin expression in V162del ferroportin disease. Hepatology 2005;42:466-72.
30. Fernandes A, Preza GC, Phung Y, et al. The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood 2009;114:437-43.
31. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399-408.
32. Lebron JA, West AP Jr, Bjorkman PJ. The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J Mol Biol 1999;294:239-45.
33. Giannetti AM, Bjorkman PJ. HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. J Biol Chem 2004;279:25866-75.
34. Vujic Spasic M, Kiss J, Herrmann T, et al. Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab 2008;7:173-8.
35. Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000; 25:14-5.
36. Fleming RE, Ahmann JR,Migas MC, et al. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc Natl Acad Sci U S A 2002;99:10653-8.
37. Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem 2006;281: 28494-8.
38. Gao J, Chen J, De Domenico I, et al. Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. Blood 2010;115:3374-81.
39. Schmidt PJ, Toran PT, Giannetti AM, et al. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab 2008;7:205-14.
40. Gao J, Chen J, Kramer M, et al. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab 2009;9:217-27.
41. Calzolari A, Raggi C, Deaglio S, et al. TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. J Cell Sci 2006;119:4486-98.
42. Ramey G, Deschemin JC, Vaulont S. Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes. Haematologica 2009; 94:765-72.
43. Poli M, Luscieti S, Gandini V, et al. Transferrin receptor 2 and HFE regulate furin expression via mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) signaling. Implications for transferrin-dependent hepcidin regulation. Haematologica 2010; 95:1832-40.
44. Wallace DF, Summerville L, Crampton EM, et al. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology 2009;50: 1992-2000.
45. Corradini E, Meynard D, Wu Q, et al. Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology 2011;54:273-84.
46. Ahmad KA, Ahmann JR, Migas MC, et al. Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol Dis 2002;29: 361-6.
47. Muckenthaler M, Roy CN, Custodio AO, et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet 2003;34:102-7.
48. Schmidt PJ, Andrews NC, Fleming MD. Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin. Blood 2010;116:5679-87.
49. Goya N, Miyazaki S, Kodate S, et al. A family of congenital atransferrinemia. Blood 1972;40:239-45.
50. Bernstein SE. Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia. J Lab Clin Med 1987;110:690-705.
51. Levy JE, Jin O, Fujiwara Y, et al. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet 1999;21:396-9.
52. Pak M, Lopez MA, Gabayan V, et al. Suppression of hepcidin during anemia requires erythropoietic activity. Blood 2006;108: 3730-5.
53. Trenor CC III, Campagna DR, Sellers VM, et al. The molecular defect in hypotransferrinemic mice. Blood 2000;96:1113-8.
54. Bartnikas TB, Fleming MD. Hemojuvelin is essential for transferrindependent and transferrin-independent hepcidin expression in mice. Haematologica 2012;97:189-92.
55. Roy CN, Weinstein DA, Andrews NC. 2002 E. Mead Johnson Award for Research in Pediatrics Lecture: the molecular biology of the anemia of chronic disease: a hypothesis. Pediatr Res 2003; 53:507-12.
56. Bartnikas TB, Andrews NC, Fleming MD. Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice. Blood 2011;117:630-7.
57. Ramos E, Kautz L, Rodriguez R, et al. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology 2011;53:1333-41.
58. D'Alessio F, Hentze MW, Muckenthaler MU. The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. J Hepatol 2012;57:1052-60.
59. Huang FW, Rubio-Aliaga I, Kushner JP, et al. Identification of a novel mutation (C321X) in HJV. Blood 2004;104:2176-7.
60. Lanzara C, Roetto A, Daraio F, et al. Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 2004;103: 4317-21.
61. Huang FW, Pinkus JL, Pinkus GS, et al. A mouse model of juvenile hemochromatosis. J Clin Invest 2005;115:2187-91.
62. Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest 2005;115:2180-6.
63. Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006;38:531-9.
64. Babitt JL, Huang FW, Xia Y, et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 2007;117:1933-9.
65. Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2005;2:399-409.
66. Kautz L, Meynard D, Monnier A, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 2008;112:1503-9.
67. Meynard D, Kautz L, Darnaud V, et al. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 2009; 41:478-81.
68. Andriopoulos B Jr, Corradini E, Xia Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 2009;41:482-7.
69. Zhang AS, Anderson SA, Wang J, et al. Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein. Blood 2011;117: 1687-99.
70. Enns CA, Ahmed R, Wang J, et al. Increased iron loading induces Bmp6 expression in the non-parenchymal cells of the liver independent of the BMP-signaling pathway. PLoS One 2013;8:e60534.
71. Knittel T, Fellmer P, Muller L, et a. l.
72. Exp Cell Res 1997;232:263-9.
73. Feng Q, Migas MC, Waheed A, et al. Ferritin upregulates hepatic expression of bone morphogenetic protein 6 and hepcidin in mice. Am J Physiol Gastrointest Liver Physiol 2012;302:G1397-404.
74. Kautz L, Meynard D, Besson-Fournier C, et al. BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood 2009;114:2515-20.
75. Corradini E, Garuti C, Montosi G, et al. Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. Gastroenterology 2009;137:1489-97.
76. Zhang AS, Gao J, Koeberl DD, et al. The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein-6 and hepcidin expression in vivo. J Biol Chem 2010;285:16416-23.
77. Steinbicker AU, Bartnikas TB, Lohmeyer LK, et al. Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. Blood 2011;118:4224-30.
78. Xia Y, Babitt JL, Sidis Y, et al. Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 2008;111:5195-204.
79. Mleczko-Sanecka K, Casanovas G, Ragab A, et al. SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood 2010;115:2657-65.
80. Ryan JD, Ryan E, Fabre A, et al. Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis. Hepatology 2010;52:1266-73.
81. Bolondi G, Garuti C, Corradini E, et al. Altered hepatic BMP signaling pathway in human HFE hemochromatosis. Blood Cells Mol Dis 2010;45:308-12.
82. Finberg KE, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008;40:569-71.
83. Tanaka T, Roy CN, Yao W, et al. A genome-wide association analysis of serum iron concentrations. Blood 2010;115:94-6.
84. Nai A, Pagani A, Silvestri L, et al. TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. Blood 2011;118:4459-62.
85. Chambers JC, ZhangW, Li Y, et al. Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat Genet 2009;41:1170-2.
86. Ganesh SK, Zakai NA, van Rooij FJ, et al. Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet 2009; 41:1191-8.
87. Folgueras AR, de Lara FM, Pendas AM, et al. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 2008;112:2539-45.
88. Du X, She E, Gelbart T, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 2008;320:1088-92.
89. Lenoir A, Deschemin JC, Kautz L, et al. Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6. Blood 2011;117:647-50.
90. Truksa J, Gelbart T, Peng H, et al. Suppression of the hepcidinencoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6. Br J Haematol 2009;147: 571-81.
91. Finberg KE, Whittlesey RL, Fleming MD, et al. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 2010;115:3817-26.
92. Silvestri L, Pagani A, Nai A, et al. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab 2008;8:502-11.
93. Enns CA, Ahmed R, Zhang AS. Neogenin interacts with matriptase- 2 to facilitate hemojuvelin cleavage. J Biol Chem 2012;287: 35104-17.
94. Beliveau F, Brule C, Desilets A, et al. Essential role of endocytosis of the type II transmembrane serine protease TMPRSS6 in regulating its functionality. J Biol Chem 2011;286:29035-43.
95. Maxson JE, Enns CA, Zhang AS. Processing of hemojuvelin requires retrograde trafficking to the Golgi in HepG2 cells. Blood 2009;113:1786-93.
96. Lee DH, Zhou LJ, Zhou Z, et al. Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis. Blood 2010;115:3136-45.
97. Santos PC, Cancado RD, Pereira AC, et al. HJV hemochromatosis, iron overload, and hypogonadism in a Brazilian man: treatment with phlebotomy and deferasirox. Acta Haematol 2010;124:204-5.
98. Fabio G, Minonzio F, Delbini P, et al. Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Blood 2007;109:362-4.
99. Maeda T, Nakamaki T, Saito B, et al. Hemojuvelin hemochromatosis receiving iron chelation therapy with deferasirox: improvement of liver disease activity, cardiac and hematological function. Eur J Haematol 2011;87:467-9.
100. Phatak P, Brissot P, Wurster M, et al. A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis. Hepatology 2010;52:1671-779.
101. Nielsen P, Fischer R, Buggisch P, et al. Effective treatment of hereditary haemochromatosis with desferrioxamine in selected cases. Br J Haematol 2003;123:952-3.
102. Gardenghi S, Ramos P,Marongiu MF, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice. J Clin Invest 2010;120:4466-77.
103. Preza GC, Ruchala P, Pinon R, et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest 2011;121:4880-8.
104. Ramos E, Ruchala P, Goodnough JB, et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood 2012;120:3829-36.
105. Corradini E, Schmidt PJ, Meynard D, et al. BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology 2010;139:1721-9.
106. 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;121:1200-8.