Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice

Journal of Clinical Investigation

Volumn 123, Issue 4, 2013, Pages 1531-1541

  Guo, Shuling ^a   Casu, Carla ^b   Gardenghi, Sara ^b   Booten, Sheri ^a   Aghajan, Mariam ^a   Peralta, Raechel ^a   Watt, Andy ^a   Freier, Sue ^a   Monia, Brett P ^a   Rivella, Stefano ^b  

^a ISIS PHARMACEUTICALS   (United States)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; ERYTHROPOIETIN; GLOBIN; HEMOGLOBIN; IRON; MATRIPTASE; REACTIVE OXYGEN METABOLITE; TMPRSS6 PROTEIN; TRANSFERRIN; UNCLASSIFIED DRUG;

ANEMIA; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTISENSE THERAPY; APOPTOSIS; ARTICLE; BETA THALASSEMIA; COMPETITIVE INHIBITION; CONTROLLED STUDY; ERYTHROPOIESIS; HEMOCHROMATOSIS; IRON BLOOD LEVEL; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SPLENOMEGALY;

ANIMALS; ANTIMICROBIAL CATIONIC PEPTIDES; BETA-THALASSEMIA; CELLS, CULTURED; FEMALE; GENE KNOCKDOWN TECHNIQUES; HEMOCHROMATOSIS; HEPATOCYTES; HISTOCOMPATIBILITY ANTIGENS CLASS I; IRON; LIVER; MALE; MEMBRANE PROTEINS; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; OLIGONUCLEOTIDES, ANTISENSE; RNA, MESSENGER; SERINE ENDOPEPTIDASES; SPLEEN; TRANSFERRIN;

EID: 84875849962     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI66969     Document Type: Article

References (61)

1. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341(26):1986-1995.
2. Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annu Rev Nutr. 2006;26:323-342.
3. Zhang AS, Enns CA. Molecular mechanisms of normal iron homeostasis. Hematology Am Soc Hematol Educ Program. 2009;2009(1):207-214.
4. Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu Rev Med. 2011;62:347-360.
5. Krause A, et al. LEAP-1, a novel highly disulfidebonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480(2-3):147-150.
6. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276(11):7806-7810.
7. Gardenghi S, Grady RW, Rivella S. Anemia, ineffective erythropoiesis, and hepcidin: Interacting factors in abnormal iron metabolism leading to iron overload in ®-thalassemia. Hematol Oncol Clin North Am. 2010;24(6):1089- 1107.
8. Ginzburg Y, Rivella S. beta-thalassemia: A model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism. Blood. 2011; 118(16):4321-4330.
9. Nemeth E, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090-2093.
10. Babitt JL, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38(5):531-539.
11. Andriopoulos B, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41(4):482-487.
12. Steinbicker AU, et al. Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. Blood. 2011;118(15):4224-4230.
13. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J Clin Invest. 2005;115(8):2187-2191.
14. 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(8):2180-2186.
15. Zhang AS, Gao J, Koeberl DD, Enns CA. The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein-6 and hepcidin expression in vivo. J Biol Chem. 2010;285(22):16416-16423.
16. Du X, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008; 320(5879):1088-1092.
17. 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):502-511.
18. Finberg KE, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008;40(5):569-571.
19. Finberg KE, Whittlesey RL, Fleming MD, Andrews NC. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood. 2010;115(18):3817-3826.
20. Maxson JE, Chen J, Enns CA, Zhang AS. Matriptase-2-and proprotein convertase-cleaved forms of hemojuvelin have different roles in the down-regulation of hepcidin expression. J Biol Chem. 2010; 285(50):39021-39028.
21. Vujic Spasic M, et al. Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab. 2008; 7(2):173-178.
22. Feder JN, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4):399-408.
23. Ramos P, et al. Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis. Blood. 2011; 117(4):1379-1389.
24. Brissot P. [Haemochromatoses. New understanding, new treatments]. Gastroenterol Clin Biol. 2009; 33(8-9):859-867.
25. Rivella S. The role of ineffective erythropoiesis in non-transfusion- dependent thalassemia. Blood Rev. 2012;26(suppl 1):S12-S15.
26. Gardenghi S, et al. Increased hepcidin expression in mice affected by ®-thalassemia reduces iron overload with no effect on anemia. Blood. 2008;112(1):53.
27. Libani IV, et al. Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia. Blood. 2008;112(3):875-885.
28. Rivella S. Ineffective erythropoiesis and thalassemias. Curr Opin Hematol. 2009;16(3):187-194.
29. Gardenghi S, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice. J Clin Invest. 2010;120(12):4466-4477.
30. Parrow NL, Gardenghi S, Rivella S. Prospects for a hepcidin mimic to treat beta-thalassemia and hemochromatosis. Expert Rev Hematol. 2011;4(3):233-235.
31. Finberg KE, Whittlesey RL, Andrews NC. Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. Blood. 2011;117(17):4590-4599.
32. Nai A, et al. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia. Blood. 2012;119(21):5021-5029.
33. Kautz L, 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(4):1503-1509.
34. Parrow NL, et al. Decreased hepcidin expression in murine beta-thalassemia is associated with suppression of Bmp/Smad signaling. Blood. 2012; 119(13):3187-3189.
35. Frazer DM, Wilkins SJ, Darshan D, Badrick AC, McLaren GD, Anderson GJ. 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):615-626.
36. Bennett CF, Swayze EE. RNA targeting therapeutics: Molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol. 2010;50:259-293.
37. Enns CA, Ahmed R, Zhang AS. Neogenin interacts with matriptase-2 to facilitate hemojuvelin cleavage. J Biol Chem. 2012;287(42):35104-35117.
38. Wood AD, et al. ID1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signaling. Blood. 2009; 114(9):1820-1830.
39. Tanno T, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13(9):1096-1101.
40. Hooper JD, Campagnolo L, Goodarzi G, Truong TN, Stuhlmann H, Quigley JP. Mouse matriptase-2: Identification, characterization and comparative mRNA expression analysis with mouse hepsin in adult and embryonic tissues. Biochem J. 2003; 373(pt 3):689-702.
41. Casanovas G, et al. The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice. Haematologica. 2013;98(3):444-447.
42. Feder JN, et al. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem. 1997;272(22):14025-14028.
43. Porto G, da Silva BM, Vincente C, de Sousa M. Idiopathic haemochromatosis in north Portugal: Association with haplotype A3B7. J Clin Pathol. 1989;42(6):667-668.
44. Brissot P, de Bels F. Current approaches to the management of hemochromatosis. Hematology Am Soc Hematol Educ Program. 2006;2006(1):36-41.
45. Gan EK, Powell LW, Olynyk JK. Natural history and management of HFE-hemochromatosis. Semin Liver Dis. 2011;31(3):293-301.
46. Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol. 2009;122(2-3):78-86.
47. Centers for Disease Control and Prevention. Hemochromatosis (Iron Storage Disease). CDC Web site. http://www.cdc.gov/ncbddd/hemochromatosis/training/ treatment/monitoring-treatment. html. Updated September 23, 2010. Accessed February 11, 2013.
48. Weatherall DJ. The definition and epidemiology of non-transfusion- dependent thalassemia. Blood Rev. 2012;26(suppl 1):S3-S6.
49. Taher AT, Musallam KM, Karimi M, Cappellini MD. Contemporary approaches to treatment of beta-thalassemia intermedia. Blood Rev. 2012; 26(suppl 1):S24-S27.
50. Taher AT, Cappellini MD, Musallam KM. Recent advances and treatment challenges in patients with non-transfusion-dependent thalassemia. Blood Rev. 2012;26(suppl 1):S1-S2.
51. Roy CN, Mak HH, Akpan I, Losyev G, Zurakowski D, Andrews NC. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood. 2007;109(9):4038-4044.
52. Corradini E, et al. BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology. 2010;139(5):1721-1729.
53. Preza GC, 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(12):4880-4888.
54. Ramos E, et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood. 2012;120(18):3829-3836.
55. Li H, et al. Transferrin therapy ameliorates disease in beta-thalassemic mice. Nat Med. 2010;16(2):177-182.
56. Cox LA, Adrian GS. Posttranscriptional regulation of chimeric human transferrin genes by iron. Biochemistry. 1993;32(18):4738-4745.
57. Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol. 1998;35(1):35-54.
58. Morton AG, Tavill AS. The control of hepatic iron uptake: Correlation with transferring synthesis. Br J Haematol. 1978;39(4):497-507.
59. Schmidt PJ, 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):1200-1208.
60. Quistorff B, Dich J, Grunnet N. Preparation of isolated rat liver hepatocytes. Methods Mol Biol. 1990;5:151-160.
61. Chen K, Liu J, Heck S, Chasis JA, An X, Mohandas N. Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc Natl Acad Sci U S A. 2009;106(41):17413-17418.