Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance

Journal of Clinical Investigation

Volumn 117, Issue 7, 2007, Pages 1933-1939

  Babitt, Jodie L ^a   Huang, Franklin W ^b   Xia, Yin ^a   Sidis, Yisrael ^a   Andrews, Nancy C ^b   Lin, Herbert Y ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b BOSTON CHILDREN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BONE MORPHOGENETIC PROTEIN 2; FERROPORTIN 1; HEMOJUVELIN; HEPCIDIN; HYBRID PROTEIN; IMMUNOGLOBULIN G; IRON; TRANSFORMING GROWTH FACTOR BETA;

ANEMIA; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG MECHANISM; IRON BALANCE; IRON BLOOD LEVEL; IRON KINETICS; IRON OVERLOAD; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN INDUCTION; SIGNAL TRANSDUCTION;

ANIMALS; ANTIMICROBIAL CATIONIC PEPTIDES; BONE MORPHOGENETIC PROTEINS; CATION TRANSPORT PROTEINS; CELL LINE; GENE EXPRESSION REGULATION; HUMANS; INTERLEUKIN-6; IRON; LIGANDS; MEMBRANE PROTEINS; MICE; RETICULOENDOTHELIAL SYSTEM; SIGNAL TRANSDUCTION; SOLUBILITY; TRANSFORMING GROWTH FACTOR BETA;

EID: 34447137331     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI31342     Document Type: Article

References (52)

1. Weiss, G., and Goodnough, L.T. 2005. Anemia of chronic disease. N. Engl. J. Med. 352:1011-1023.
2. Pigeon, C., et al. 2001. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J. Biol. Chem. 276:7811-7819.
3. Nicolas, G., et al. 2002. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J. Clin. Invest. 110:1037-1044. doi:10.1172/JCI200215686.
4. Nemeth, E., et al. 2004. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113:1271-1276. doi:10.1172/JCI200420945.
5. Nemeth, E., et al. 2003. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 101:2461-2463.
6. Lee, P., Peng, H., Gelbart, T., Wang, L., and Beutler, E. 2005. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc. Natl. Acad. Sci. U. S. A. 102:1906-1910.
7. Hentze, M.W., Muckenthaler, M.U., and Andrews, N.C. 2004. Balancing acts: molecular control of mammalian iron metabolism. Cell. 117:285-297.
8. Krause, A., et al. 2000. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 480:147-150.
9. Park, C.H., Valore, E.V., Waring, A.J., and Ganz, T. 2001. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276:7806-7810.
10. Nemeth, E., et al. 2004. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 306:2090-2093.
11. Pietrangelo, A. 2006. Hereditary hemochromatosis. Biochim. Biophys. Acta. 1763:700-710.
12. Roetto, A., et al. 2003. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat. Genet. 33:21-22.
13. Papanikolaou, G., et al. 2004. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat. Genet. 36:77-82.
14. Huang, F.W., Pinkus, J.L., Pinkus, G.S., Fleming, M.D., and Andrews, N.C. 2005. A mouse model of juvenile hemochromatosis. J. Clin. Invest. 115:2187-2191. doi:10.1172/JCI25049.
15. Niederkofler, V., Salie, R., and Arber, S. 2005. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J. Clin. Invest. 115:2180-2186. doi:10.1172/JCI25683.
16. Ahmad, K.A., et al. 2002. Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol. Dis. 29:361-366.
17. Bridle, K.R., et al. 2003. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 361:669-673.
18. Muckenthaler, M., et al. 2003. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat. Genet. 34:102-107.
19. Nicolas, G., et al. 2003. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat. Genet. 34:97-101.
20. Kawabata, H., et al. 2005. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood. 105:376-381.
21. Nemeth, E., Roetto, A., Garozzo, G., Ganz, T., and Camaschella, C. 2005. Hepcidin is decreased in TFR2 hemochromatosis. Blood. 105:1803-1806.
22. Babitt, J.L., et al. 2006. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38:531-539.
23. Wang, R.H., et al. 2005. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2:399-409.
24. Truksa, J., Peng, H., Lee, P., and Beutler, E. 2006. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc. Natl. Acad. Sci. U. S. A. 103:10289-10293.
25. Shi, Y., and Massague, J. 2003. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 113:685-700.
26. Monnier, P.P., et al. 2002. RGM is a repulsive guidance molecule for retinal axons. Nature. 419:392-395.
27. Samad, T.A., et al. 2004. DRAGON: a member of the repulsive guidance molecule-related family of neuronal- and muscle-expressed membrane proteins is regulated by DRG11 and has neuronal adhesive properties. J. Neurosci. 24:2027-2036.
28. Samad, T.A., et al. 2005. DRAGON, a bone morphogenetic protein co-receptor. J. Biol. Chem. 280:14122-14129.
29. Babitt, J.L., et al. 2005. Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J. Biol. Chem. 280:29820-29827.
30. Korchynskyi, O., and ten Dijke, P. 2002. Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J. Biol. Chem. 277:4883-4891.
31. Dennler, S., et al. 1998. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J. 17:3091-3100.
32. Moreland, L.W., et al. 1997. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N. Engl. J. Med. 337:141-147.
33. Lin, L., Goldberg, Y.P., and Ganz, T. 2005. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood. 106:2884-2889.
34. Roy, C.N., et al. 2004. An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice. Nat. Genet. 36:481-485.
35. Wyeth Pharmaceuticals Inc. 2004. Summary of safety and effectiveness data for INFUSE bone graft. http://www.fda.gov/cdrh/PDF4/p000054b.pdf.
36. De Bleser, P.J., Niki, T., Rogiers, V., and Geerts, A. 1997. Transforming growth factor-beta gene expression in normal and fibrotic rat liver. J. Hepatol. 26:886-893.
37. Kingsley, D.M. 1994. What do BMPs do in mammals? Clues from the mouse short-ear mutation. Trends Genet. 10:16-21.
38. Knittel, T., Fellmer, P., Muller, L., and Ramadori, G. 1997. Bone morphogenetic protein-6 is expressed in nonparenchymal liver cells and upregulated by transforming growth factor-beta 1. Exp. Cell Res. 232:263-269.
39. Su, A.I., et al. 2002. Large-scale analysis of the human and mouse transcriptomes. Proc. Natl. Acad. Sci. U. S. A. 99:4465-4470.
40. Miller, A.F., Harvey, S.A., Thies, R.S., and Olson, M.S. 2000. Bone morphogenetic protein-9. An autocrine/paracrine cytokine in the liver. J. Biol. Chem. 275:17937-17945.
41. Zhang, A.S., West, A.P., Jr. Wyman, A.E., Bjorkman, P.J., and Enns, C.A. 2005. Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J. Biol. Chem. 280:33885-33894.
42. Wrighting, D.M., and Andrews, N.C. 2006. Interleukin-6 induces hepcidin expression through STAT3. Blood. 108:3204-3209.
43. Verga Falzacappa, M.V., et al. 2007. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 109:353-358.
44. Pietrangelo, A., et al. 2007. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology. 132:294-300.
45. Bosukonda, D., Shih, M.S., Sampath, K.T., and Vukicevic, S. 2000. Characterization of receptors for osteogenic protein-1/bone morphogenetic protein-7 (OP-1/BMP-7) in rat kidneys. Kidney Int. 58:1902-1911.
46. Hruska, K.A., et al. 2000. Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am. J. Physiol. Renal Physiol. 279:F130-F143.
47. Morrissey, J., et al. 2002. Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J. Am. Soc. Nephrol. 13(Suppl. 1):S14-S21.
48. Vukicevic, S., et al. 1998. Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat. J. Clin. Invest. 102:202-214.
49. Zeisberg, M., et al. 2003. Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am. J. Physiol. Renal Physiol. 285:F1060-F1067.
50. Torrance, J.D., and Bothwell, T.H. 1980. Tissue iron stores. Methods Hematol. 1:90-115.
51. Canonne-Hergaux, F., Gruenheid, S., Ponka, P., and Gros, P. 1999. Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood. 93:4406-4417.
52. Canonne-Hergaux, F., Donovan, A., Delaby, C., Hui-jun, W., and Gros, P. 2005. Comparative studies of duodenal and macrophage ferroportin proteins. Am. J. Physiol. Gastrointest. Liver Physiol. 290:156-163.