Hepcidin antagonists for potential treatments of disorders with hepcidin excess

Frontiers in Pharmacology

Volumn 5 APR, Issue , 2014, Pages

  Poli, Maura ^a   Asperti, Michela ^a   Ruzzenenti, Paola ^a   Regoni, Maria ^a   Arosio, Paolo ^a  

^a UNIVERSITY OF BRESCIA   (Italy)

Author keywords

Anemia of chronic diseases; Heparin; Hepcidin; Inflammation; Iron metabolism

Indexed keywords

ADENINE; BONE MORPHOGENETIC PROTEIN 6; BONE MORPHOGENETIC PROTEIN RECEPTOR; FERROPORTIN; GROWTH DIFFERENTIATION FACTOR 15; HEPARIN DERIVATIVE; HEPCIDIN; HEPCIDIN ANTAGONIST; HEPCIDIN INHIBITOR; INTERLEUKIN 6; LIPOPOLYSACCHARIDE; PROTEIN INHIBITOR; PROTEOGLYCAN; SMAD PROTEIN; STAT3 PROTEIN; TURPENTINE; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; ANEMIA; BRUCELLA ABORTUS; CARBOXY TERMINAL SEQUENCE; CENTRAL NERVOUS SYSTEM; DISEASE ACTIVITY; DRUG MECHANISM; DRUG SYNTHESIS; GENETIC MODEL; HEPCIDIN EXCESS; HUMAN; INFLAMMATORY ANEMIA; INFLAMMATORY DISEASE; KIDNEY DISEASE; NEUROMODULATION; NONHUMAN; PROTEIN DEFECT; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REVIEW; UPREGULATION;

EID: 84901046083     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2014.00086     Document Type: Review

References (124)

1. Akinc, A., Chan-Daniels, A., Sehgal, A., Foster, D., Bettencourt, B. R., Hettinger, J., et al. (2011). Targeting the hepcidin pathway with RNAi therapeutics for the treatment of anemia. Blood 118:315.
2. Andriopoulos, B. J., Corradini, E., Xia, Y., Faasse, S., Chen, S., Grgurevic, L., et al. (2009). BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat. Genet. 41, 482-487. doi: 10.1038/ng.335
3. Armitage, A. E., Eddowes, L. A., Gileadi, U., Cole, S., Spottiswoode, N., Selvakumar, T. A., et al. (2011). Hepcidin regulation by innate immune and infectious stimuli. Blood 118, 4129-4139. doi: 10.1182/blood-2011-04-351957
4. Babitt, J., Huang, F., Wrighting, D., Xia, Y., Sidis, Y., Samad, T., et al. (2006). Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38, 531-539. doi: 10.1038/ng1777
5. Babitt, J. L., Huang, F. W., Xia, Y., Sidis, Y., Andrews, N. C., and Lin, H. Y. (2007). Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J. Clin. Invest. 117, 1933-1939. doi: 10.1172/JCI31342
6. Berg, D., Gerlach, M., Youdim, M. B., Double, K. L., Zecca, L., Riederer, P., et al. (2001). Brain iron pathways and their relevance to Parkinson's disease. J. Neurochem. 79, 225-236. doi: 10.1046/j.1471-4159.2001.00608.x
7. Besson-Fournier, C., Latour, C., Kautz, L., Bertrand, J., Ganz, T., Roth, M. P., et al. (2012). Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling. Blood 120, 431-439. doi: 10.1182/blood-2012-02-411470
8. Bishop, G. M., Robinson, S. R., Liu, Q., Perry, G., Atwood, C. S., and Smith, M. A. (2002). Iron: a pathological mediator of Alzheimer disease? Dev. Neurosci. 24, 184-187. doi: 10.1159/000065696
9. Caceres-Cortes, J. R. (2008). A potent anti-carcinoma and anti-acute myeloblastic leukemia agent, AG490. Anticancer Agents Med. Chem. 8, 717-722. doi: 10.2174/187152008785914752
10. Casanovas, G., Spasic, M. V., Casu, C., Rivella, S., Strelau, J., Unsicker, K., et al. (2013). The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice. Haematologica 98, 444-447. doi: 10.3324/haematol.2012.069807
11. Casu, B., Naggi, A., and Torri, G. (2002). Chemical derivatization as a strategy to study structure-activity relationships of glycosaminoglycans. Semin. Thromb. Hemost. 28, 335-342. doi: 10.1055/s-2002-34302
12. Casu, B., Naggi, A., and Torri, G. (2010). Heparin-derived heparan sulfate mimics to modulate heparan sulfate-protein interaction in inflammation and cancer. Matrix Biol. 29, 442-452. doi: 10.1016/j.matbio.2010.04.003
13. Choi, Y. K., and Kim, K. W. (2008). Blood-neural barrier: its diversity and coordinated cell-to-cell communication. BMB Rep. 41, 345-352.
14. Chung, B., Verdier, F., Matak, P., Deschemin, J. C., Mayeux, P., and Vaulont, S. (2010). Oncostatin M is a potent inducer of hepcidin, the iron regulatory hormone. FASEB J. 24, 2093-2103. doi: 10.1096/fj.09-152561
15. Clardy, S. L., Earley, C. J., Allen, R. P., Beard, J. L., and Connor, J. R. (2006). Ferritin subunits in CSF are decreased in restless legs syndrome. J. Lab. Clin. Med. 147, 67-73. doi: 10.1016/j.lab.2005.06.011
16. Cooke, K. S., Hinkle, B., Salimi-Moosavi, H., Foltz, I., King, C., Rathanaswami, P., et al. (2013). A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates. Blood 122, 3054-3061. doi: 10.1182/blood-2013-06-505792
17. Corradini, E., Babitt, J. L., and Lin, H. Y. (2009). The RGM/DRAGON family of BMP co-receptors. Cytokine Growth Factor Rev. 20, 389-398. doi: 10.1016/j.cytogfr.2009.10.008
18. Corradini, E., Schmidt, P. J., Meynard, D., Garuti, C., Montosi, G., Chen, S., et al. (2010). BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology 139, 1721-1729. doi: 10.1053/j.gastro.2010.07.044
19. Cromartie, W. J., Craddock, J. G., Schwab, J. H., Anderle, S. K., and Yang, C. H. (1977). Arthritis in rats after systemic injection of streptococcal cells or cell walls. J. Exp. Med. 146, 1585-1602. doi: 10.1084/jem.146.6.1585
20. Cuny, G. D., Yu, P. B., Laha, J. K., Xing, X., Liu, J. F., Lai, C. S., et al. (2008). Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors. Bioorg. Med. Chem. Lett. 18, 4388-4392. doi: 10.1016/j.bmcl.2008.06.052
21. De Domenico, I., Ward, D., Nemeth, E., Vaughn, M., Musci, G., Ganz, T., et al. (2005). The molecular basis of ferroportin-linked hemochromatosis. Proc. Natl. Acad. Sci. U.S.A. 102, 8955-8960. doi: 10.1073/pnas.0503804102
22. Ding, H., Yan, C. Z., Shi, H., Zhao, Y. S., Chang, S. Y., Yu, P., et al. (2011). Hepcidin is involved in iron regulation in the ischemic brain. PLoS ONE 6:e25324. doi: 10.1371/journal.pone.0025324
23. Du, X., She, E., Gelbart, T., Truksa, J., Lee, P., Xia, Y., et al. (2008). The serine protease TMPRSS6 is required to sense iron deficiency. Science 320, 1088-1092. doi: 10.1126/science.1157121
24. Edelhauser, H. F., Rowe-Rendleman, C. L., Robinson, M. R., Dawson, D. G., Chader, G. J., Grossniklaus, H. E., et al. (2010). Ophthalmic drug delivery systems for the treatment of retinal diseases: basic research to clinical applications. Invest. Ophthalmol. Vis. Sci. 51, 5403-5420. doi: 10.1167/iovs.10-5392
25. Enns, C. A., Ahmed, R., and Zhang, A. S. (2012). Neogenin interacts with matriptase-2 to facilitate hemojuvelin cleavage. J. Biol. Chem. 287, 35104-35117. doi: 10.1074/jbc. M112.363937
26. Fatih, N., Camberlein, E., Island, M., Corlu, A., Abgueguen, E., Détivaud, L., et al. (2010). Natural and synthetic STAT3 inhibitors reduce hepcidin expression in differentiated mouse hepatocytes expressing the active phosphorylated STAT3 form. J. Mol. Med. 88, 477-486. doi: 10.1007/s00109-009-0588-3
27. Fernandes, A., Preza, G. C., Phung, Y., De Domenico, I., Kaplan, J., Ganz, T., et al. (2009). The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood 114, 437-443. doi: 10.1182/blood-2008-03-146134
28. Finberg, K. E., Heeney, M. M., Campagna, D. R., Aydinok, Y., Pearson, H. A., Hartman, K. R., et al. (2008). Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat. Genet. 40, 569-571. doi: 10.1038/ng.130
29. Fleming, R. E., and Sly, W. S. (2001). Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc. Natl. Acad. Sci. U.S.A. 98, 8160-8162. doi: 10.1073/pnas.161296298
30. Flower, D. R. (1996). The lipocalin protein family: structure and function. Biochem. J. 318(Pt 1), 1-14.
31. Folgueras, A. R., de Lara, F. M., Pendás, A. M., Garabaya, C., Rodrïguez, F., Astudillo, A., et al. (2008). Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 112, 2539-2545. doi: 10.1182/blood-2008-04-149773
32. Fujiwara, T., Ikeda, T., Nagasaka, Y., Okitsu, Y., Katsuoka, Y., Fukuhara, N., et al. (2013). A low-molecular-weight compound K7174 represses hepcidin: possible therapeutic strategy against anemia of chronic disease. PLoS ONE 8:e75568. doi: 10.1371/journal.pone.0075568
33. Fung, E., and Nemeth, E. (2013). Manipulation of the hepcidin pathway for therapeutic purposes. Haematologica 98, 1667-1676. doi: 10.3324/haematol.2013.084624
34. Fung, E., Sugianto, P., Hsu, J., Damoiseaux, R., Ganz, T., and Nemeth, E. (2013). High-throughput screening of small molecules identifies hepcidin antagonists. Mol. Pharmacol. 83, 681-690. doi: 10.1124/mol.112.083428
35. Ganz, T., and Nemeth, E. (2011). Hepcidin and disorders of iron metabolism. Annu. Rev. Med. 62, 347-360. doi: 10.1146/annurev-med-050109-142444
36. Ganz, T., and Nemeth, E. (2012). Hepcidin and iron homeostasis. Biochim. Biophys. Acta 1823, 1434-1443. doi: 10.1016/j.bbamcr.2012.01.014
37. Gao, J., Chen, J., De Domenico, I., Koeller, D. M., Harding, C. O., Fleming, R. E., et al. (2010). Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. Blood 115, 3374-3381. doi: 10.1182/blood-2009-09-245209
38. Gardenghi, S., Renaud, T. M., Meloni, A., Casu, C., Crielaard, B. J., Bystrom, L. M., et al. (2014). Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood 123, 1137-1145. doi: 10.1182/blood-2013-08-521625
39. Glaspy, J. (2012). Update on safety of ESAs in cancer-induced anemia. J. Natl. Compr. Canc. Netw. 10, 659-666.
40. Goodnough, L. T., Nemeth, E., and Ganz, T. (2010). Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 116, 4754-4761. doi: 10.1182/blood-2010-05-286260
41. Hashizume, M., Uchiyama, Y., Horai, N., Tomosugi, N., and Mihara, M. (2010). Tocilizumab, a humanized anti-interleukin-6 receptor antibody, improved anemia in monkey arthritis by suppressing IL-6-induced hepcidin production. Rheumatol. Int. 30, 917-923. doi: 10.1007/s00296-009-1075-4
42. Hayflick, S. (2006). Neurodegeneration with brain iron accumulation: from genes to pathogenesis. Semin. Pediatr. Neurol. 13, 182-185. doi: 10.1016/j.spen.2006.08.007
43. Hentze, M. W., Muckenthaler, M. U., Galy, B., and Camaschella, C. (2010). Two to tango: regulation of Mammalian iron metabolism. Cell 142, 24-38. doi: 10.1016/j.cell.2010.06.028
44. Hunter, H. N., Fulton, D. B., Ganz, T., and Vogel, H. J. (2002). The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J. Biol. Chem. 277, 37597-37603. doi: 10.1074/jbc. M205305200
45. Irie, A., Habuchi, H., Kimata, K., and Sanai, Y. (2003). Heparan sulfate is required for bone morphogenetic protein-7 signaling. Biochem. Biophys. Res. Commun. 308, 858-865. doi: 10.1016/S0006-291X(03)01500-6
46. Jiao, X., Billings, P. C., O'Connell, M. P., Kaplan, F. S., Shore, E. M., and Glaser, D. L. (2007). Heparan sulfate proteoglycans (HSPGs) modulate BMP2 osteogenic bioactivity in C2C12 cells. J. Biol. Chem. 282, 1080-1086. doi: 10.1074/jbc. M513414200
47. Jordan, J. B., Poppe, L., Haniu, M., Arvedson, T., Syed, R., Li, V., et al. (2009). Hepcidin revisited, disulfide connectivity, dynamics, and structure. J. Biol. Chem. 284, 24155-24167. doi: 10.1074/jbc. M109.017764
48. Kautz, L., Jung, G., Nemeth, E., and Ganz, T. (2013). The erythroid factor erythroferrone and its role in iron homeostasis. Blood 122:4.
49. Kim, A., Fung, E., Parikh, S. G., Valore, E. V., Gabayan, V., Nemeth, E., et al. (2014). A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood 123, 1129-1136. doi: 10.1182/blood-2013-08-521419
50. Krause, A., Neitz, S., Mägert, H., Schulz, A., Forssmann, W., Schulz-Knappe, P., et al. (2000). LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 480, 147-150. doi: 10.1016/S0014-5793(00)01920-7
51. Kuninger, D., Kuns-Hashimoto, R., Nili, M., and Rotwein, P. (2008). Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin. BMC Biochem. 9:9. doi: 10.1186/1471-2091-9-9
52. Kuo, W. J., Digman, M. A., and Lander, A. D. (2010). Heparan sulfate acts as a bone morphogenetic protein coreceptor by facilitating ligand-induced receptor hetero-oligomerization. Mol. Biol. Cell 21, 4028-4041. doi: 10.1091/mbc. E10-04-0348
53. Kurzrock, R., Voorhees, P. M., Casper, C., Furman, R. R., Fayad, L., Lonial, S., et al. (2013). A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin. Cancer Res. 19, 3659-3670. doi: 10.1158/1078-0432.CCR-12-3349
54. Lasocki, S., Millot, S., Andrieu, V., Lettéron, P., Pilard, N., Muzeau, F., et al. (2008). Phlebotomies or erythropoietin injections allow mobilization of iron stores in a mouse model mimicking intensive care anemia. Crit. Care Med. 36, 2388-2394. doi: 10.1097/CCM.0b013e31818103b9
55. Leung, D. D. M., Luan, P., Manetta, J. V., Tang, Y., and Witcher, D. R. (2012). Anti-ferroportin 1 monoclonal antibodies and uses thereof. US 8183346. Washington, DC: U.S. Patent and Trademark Office.
56. Liu, X. B., Yang, F., and Haile, D. J. (2005). Functional consequences of ferroportin 1 mutations. Blood Cells Mol. Dis. 35, 33-46. doi: 10.1016/j.bcmd.2005.04.005
57. Macdougall, I. C., and Cooper, A. C. (2002). Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol. Dial. Transplant. 17(Suppl. 11), 39-43. doi: 10.1093/ndt/17.suppl_11.39
58. Maes, K., Nemeth, E., Roodman, G. D., Huston, A., Esteve, F., Freytes, C., et al. (2010). In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood 116, 3635-3644. doi: 10.1182/blood-2010-03-274571
59. Malik, I. A., Naz, N., Sheikh, N., Khan, S., Moriconi, F., Blaschke, M., et al. (2011). Comparison of changes in gene expression of transferrin receptor-1 and other iron-regulatory proteins in rat liver and brain during acute-phase response. Cell Tissue Res. 344, 299-312. doi: 10.1007/s00441-011-1152-3
60. Meynard, D., Kautz, L., Darnaud, V., Canonne-Hergaux, F., Coppin, H., and Roth, M. P. (2009). Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat. Genet. 41, 478-481. doi: 10.1038/ng.320
61. Mleczko-Sanecka, K., Casanovas, G., Ragab, A., Breitkopf, K., Müller, A., Boutros, M., et al. (2010). SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood 115, 2657-2665. doi: 10.1182/blood-2009-09-238105
62. Montosi, G., Donovan, A., Totaro, A., Garuti, C., Pignatti, E., Cassanelli, S., et al. (2001). Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J. Clin. Invest. 108, 619-623. doi: 10.1172/JCI200113468
63. Muckenthaler, M. U. (2008). Fine tuning of hepcidin expression by positive and negative regulators. Cell Metab. 8, 1-3. doi: 10.1016/j.cmet.2008.06.009
64. Nemeth, E., and Ganz, T. (2006). Regulation of iron metabolism by hepcidin. Annu. Rev. Nutr. 26, 323-342. doi: 10.1146/annurev.nutr.26.061505.111303
65. Nemeth, E., Preza, G. C., Jung, C. L., Kaplan, J., Waring, A. J., and Ganz, T. (2006). The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood 107, 328-333. doi: 10.1182/blood-2005-05-2049
66. Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., et al. (2004). Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090-2093. doi: 10.1126/science.1104742
67. Nicolas, G., Bennoun, M., Devaux, I., Beaumont, C., Grandchamp, B., Kahn, A., et al. (2001). Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc. Natl. Acad. Sci. U.S.A. 98, 8780-8785. doi: 10.1073/pnas.151179498
68. Nicolas, G., Chauvet, C., Viatte, L., Danan, J., Bigard, X., Devaux, I., 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/JCI0215686
69. Nicolas, G., Viatte, L., Lou, D. Q., Bennoun, M., Beaumont, C., Kahn, A., et al. (2003). Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat. Genet. 34, 97-101. doi: 10.1038/ng1150
70. Papanikolaou, G., Samuels, M. E., Ludwig, E. H., MacDonald, M. L., Franchini, P. L., Dubé, M. P., et al. (2004). Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat. Genet. 36, 77-82. doi: 10.1038/ng1274
71. Park, C., Valore, E., Waring, A., and Ganz, T. (2001). Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276, 7806-7810. doi: 10.1074/jbc. M008922200
72. Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., 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. doi: 10.1074/jbc. M008923200
73. Poli, M., Asperti, M., Naggi, A., Campostrini, N., Girelli, D., Corbella, M., et al. (2014). Glycol-split non-anticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo. Blood 123, 1564-1573.
74. Poli, M., Girelli, D., Campostrini, N., Maccarinelli, F., Finazzi, D., Luscieti, S., et al. (2011). Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo. Blood 117, 997-1004. doi: 10.1182/blood-2010-06-289082
75. Poli, M., Luscieti, S., Gandini, V., Maccarinelli, F., Finazzi, D., Silvestri, L., et al. (2010). 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 95, 1832-1840. doi: 10.3324/haematol.2010.027003
76. Qiao, B., Sugianto, P., Fung, E., Del-Castillo-Rueda, A., Moran-Jimenez, M. J., Ganz, T., et al. (2012). Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab. 15, 918-924. doi: 10.1016/j.cmet.2012.03.018
77. Raha, A. A., Vaishnav, R. A., Friedland, R. P., Bomford, A., and Raha-Chowdhury, R. (2013). The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer's disease. Acta Neuropathol. Commun. 1:55. doi: 10.1186/2051-5960-1-55
78. Riecke, K., Zollner, S., Boyce, M., Vauléon, S., Swinkels, D. W., Dümmler, T., et al. (2012). Single and repeated dose first-in-human study with the antihepcidin spiegelmer NOX-H94. Blood 120:2021.
79. Ritchie, J. P., Ramani, V. C., Ren, Y., Naggi, A., Torri, G., Casu, B., et al. (2011). SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin. Cancer Res. 17, 1382-1393. doi: 10.1158/1078-0432.CCR-10-2476
80. Rivera, S., and Ganz, T. (2009). Animal models of anemia of inflammation. Semin. Hematol. 46, 351-357. doi: 10.1053/j.seminhematol.2009.06.003
81. Roetto, A., Papanikolaou, G., Politou, M., Alberti, F., Girelli, D., Christakis, J., et al. (2003). Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat. Genet. 33, 21-22. doi: 10.1038/ng1053
82. Rouault, T. A., Zhang, D. L., and Jeong, S. Y. (2009). Brain iron homeostasis, the choroid plexus, and localization of iron transport proteins. Metab. Brain Dis. 24, 673-684. doi: 10.1007/s11011-009-9169-y
83. Rusnati, M., Oreste, P., Zoppetti, G., and Presta, M. (2005). Biotechnological engineering of heparin/heparan sulphate: a novel area of multi-target drug discovery. Curr. Pharm. Des. 11, 2489-2499. doi: 10.2174/1381612054367553
84. Saeed, O., Otsuka, F., Polavarapu, R., Karmali, V., Weiss, D., Davis, T., et al. (2012). Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 32, 299-307. doi: 10.1161/ATVBAHA.111.240101
85. Sakamori, R., Takehara, T., Tatsumi, T., Shigekawa, M., Hikita, H., Hiramatsu, N., et al. (2010). STAT3 signaling within hepatocytes is required for anemia of inflammation in vivo. J. Gastroenterol. 45, 244-248. doi: 10.1007/s00535-009-0159-y
86. Sasu, B., Cooke, K., Arvedson, T., Plewa, C., Ellison, A., Sheng, J., et al. (2010). Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood 115, 3616-3624. doi: 10.1182/blood-2009-09-245977
87. Schipperus, M., Rijnbeek, B., Reddy, M., Qin, X., and Cornfield, M. J. (2009). CNTO328 (Anti-IL-6 mAb) treatment is associated with an increase in hemoglobin (Hb) and decrease in hepcidin levels in renal cell carcinoma (RCC). Blood 114:4045.
88. Schlehuber, S., and Skerra, A. (2005). Lipocalins in drug discovery: from natural ligand-binding proteins to "anticalins." Drug Discov. Today 10, 23-33. doi: 10.1016/S1359-6446(04)03294-5
89. Schwoebel, F., van Eijk, L. T., Zboralski, D., Sell, S., Buchner, K., Maasch, C., et al. (2013). The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys. Blood 121, 2311-2315. doi: 10.1182/blood-2012-09-456756
90. Shike, H., Shimizu, C., Lauth, X., and Burns, J. C. (2004). Organization and expression analysis of the zebrafish hepcidin gene, an antimicrobial peptide gene conserved among vertebrates. Dev. Comp. Immunol. 28, 747-754. doi: 10.1016/j.dci.2003.11.009
91. Silvestri, L., Guillem, F., Pagani, A., Nai, A., Oudin, C., Silva, M., et al. (2009). Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. Blood 113, 5605-5608. doi: 10.1182/blood-2008-12-195594
92. Silvestri, L., Pagani, A., and Camaschella, C. (2008). Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood 111, 924-931. doi: 10.1182/blood-2007-07-100677
93. Song, S. N., Tomosugi, N., Kawabata, H., Ishikawa, T., Nishikawa, T., and Yoshizaki, K. (2010). Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood 116, 3627-3634. doi: 10.1182/blood-2010-03-271791
94. Stanford, K., Wang, L., Castagnola, J., Song, D., Bishop, J., Brown, J., et al. (2010). Heparan sulfate 2-O-sulfotransferase is required for triglyceride-rich lipoprotein clearance. J. Biol. Chem. 285, 286-294. doi: 10.1074/jbc. M109.063701
95. Steinbicker, A. U., Sachidanandan, C., Vonner, A. J., Yusuf, R. Z., Deng, D. Y., Lai, C. S., et al. (2011). Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood 117, 4915-4923. doi: 10.1182/blood-2010-10-313064
96. Sun, C. C., Vaja, V., Babitt, J. L., and Lin, H. Y. (2011). Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation. Am. J. Hematol. 87, 392-400. doi: 10.1002/ajh.23110
97. Sun, C. C., Vaja, V., Chen, S., Theurl, I., Stepanek, A., Brown, D. E., et al. (2013). A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats. Nephrol. Dial. Transplant. 28, 1733-1743. doi: 10.1093/ndt/gfs584
98. Sun, C., Song, N., Xie, A., Xie, J., and Jiang, H. (2012). High hepcidin level accounts for the nigral iron accumulation in acute peripheral iron intoxication rats. Toxicol. Lett. 212, 276-281. doi: 10.1016/j.toxlet.2012.05.022
99. Tanno, T., Bhanu, N., Oneal, P., Goh, S., Staker, P., Lee, Y., et al. (2007). High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat. Med. 13, 1096-1101. doi: 10.1038/nm1629
100. Theurl, I., Aigner, E., Theurl, M., Nairz, M., Seifert, M., Schroll, A., et al. (2009). Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 113, 5277-5286. doi: 10.1182/blood-2008-12-195651
101. Theurl, I., Schroll, A., Sonnweber, T., Nairz, M., Theurl, M., Willenbacher, W., et al. (2011). Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. Blood 118, 4977-4984. doi: 10.1182/blood-2011-03-345066
102. 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. doi: 10.1073/pnas.0603124103
103. Turnbull, J., Powell, A., and Guimond, S. (2001). Heparan sulfate: decoding a dynamic multifunctional cell regulator. Trends Cell Biol. 11, 75-82. doi: 10.1016/S0962-8924(00)01897-3
104. Valore, E. V., and Ganz, T. (2008). Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol. Dis. 40, 132-138. doi: 10.1016/j.bcmd.2007.07.009
105. Van Eijk, L., Swinkels, D. W., John, A., Schwoebel, F., Fliegert, F., Summo, L., et al. (2013). Randomized double blind placebo controlled PK/PD study on the effects of a single intravenous dose of the anti-hepcidin spiegelmer NOX-H94 on serum iron during experimental human endotoxemia. Crit. Care 17:352. doi: 10.1186/cc12290
106. van Rhee, F., Fayad, L., Voorhees, P., Furman, R., Lonial, S., Borghaei, H., et al. (2010). Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease. J. Clin. Oncol. 28, 3701-3708. doi: 10.1200/JCO.2009.27.2377
107. Verga Falzacappa, M. V., Vujic Spasic, M., Kessler, R., Stolte, J., Hentze, M. W., and Muckenthaler, M. U. (2007). STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 109, 353-358. doi: 10.1182/blood-2006-07-033969
108. Vogt, J., Traynor, R., and Sapkota, G. P. (2011). The specificities of small molecule inhibitors of the TGFβ and BMP pathways. Cell. Signal. 23, 1831-1842. doi: 10.1016/j.cellsig.2011.06.019
109. Volman, T. J., Hendriks, T., and Goris, R. J. (2005). Zymosan-induced generalized inflammation: experimental studies into mechanisms leading to multiple organ dysfunction syndrome. Shock 23, 291-297. doi: 10.1097/01.shk.0000155350.95435.28
110. Wallace, D. F., Harris, J. M., and Subramaniam, V. N. (2010). Functional analysis and theoretical modeling of ferroportin reveals clustering of mutations according to phenotype. Am. J. Physiol. Cell Physiol. 298, C75-C84. doi: 10.1152/ajpcell.00621.2008
111. Wang, J., Lu, Z., Wientjes, M. G., and Au, J. L. (2010a). Delivery of siRNA therapeutics: barriers and carriers. AAPS J. 12, 492-503. doi: 10.1208/s12248-010-9210-4
112. Wang, S. M., Fu, L. J., Duan, X. L., Crooks, D. R., Yu, P., Qian, Z. M., et al. (2010b). Role of hepcidin in murine brain iron metabolism. Cell. Mol. Life Sci. 67, 123-133. doi: 10.1007/s00018-009-0167-3
113. Wang, L., Trebicka, E., Fu, Y., Ellenbogen, S., Hong, C. C., Babitt, J. L., et al. (2012). The bone morphogenetic protein-hepcidin axis as a therapeutic target in inflammatory bowel disease. Inflamm. Bowel Dis. 18, 112-119. doi: 10.1002/ibd.21675
114. Wang, L., Yang, H., Zhao, S., Sato, H., Konishi, Y., Beach, T. G., et al. (2011). Expression and localization of mitochondrial ferritin mRNA in Alzheimer's disease cerebral cortex. PLoS ONE 6:e22325. doi: 10.1371/journal.pone.0022325
115. Wang, R., Li, C., Xu, X., Zheng, Y., Xiao, C., Zerfas, P., et al. (2005). A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2, 399-409. doi: 10.1016/j.cmet.2005.10.010
116. Wei, S., Shi, W., Li, M., and Gao, Q. (2014). Calorie restriction down-regulates expression of the iron regulatory hormone hepcidin in normal and D-galactose-induced aging mouse brain. Rejuvenation Res. 17, 19-26. doi: 10.1089/rej.2013.1450
117. Xia, Y., Babitt, J., Sidis, Y., Chung, R., and Lin, H. (2008). Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 111, 5195-5204. doi: 10.1182/blood-2007-09-111567
118. Yu, P. B., Deng, D. Y., Lai, C. S., Hong, C. C., Cuny, G. D., Bouxsein, M. L., et al. (2008). BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat. Med. 14, 1363-1369. doi: 10.1038/nm.1888
119. Zecca, L., Youdim, M., Riederer, P., Connor, J., and Crichton, R. (2004). Iron, brain ageing and neurodegenerative disorders. Nat. Rev. Neurosci. 5, 863-873. doi: 10.1038/nrn1537
120. Zechel, S., Huber-Wittmer, K., and von Bohlen und Halbach, O. (2006). Distribution of the iron-regulating protein hepcidin in the murine central nervous system. J. Neurosci. Res. 84, 790-800. doi: 10.1002/jnr.20991
121. 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. doi: 10.1074/jbc. M506207200
122. Zhang, S. P., Wang, Z., Wang, L. X., and Liu, S. J. (2011). AG490: an inhibitor of hepcidin expression in vivo. World J. Gastroenterol. 17, 5032-5034. doi: 10.3748/wjg.v17.i45.5032
123. Zhang, X., Yue, P., Fletcher, S., Zhao, W., Gunning, P. T., and Turkson, J. (2010). A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes. Biochem. Pharmacol. 79, 1398-1409. doi: 10.1016/j.bcp.2010.01.001
124. Zhao, N., Zhang, A. S., and Enns, C. A. (2013). Iron regulation by hepcidin. J. Clin. Invest. 123, 2337-2343. doi: 10.1172/JCI67225