Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice

Hepatology

Volumn 54, Issue 1, 2011, Pages 273-284

  Corradini, Elena ^a,b   Meynard, Delphine ^a   Wu, Qifang ^a   Chen, Shan ^a   Ventura, Paolo ^b   Pietrangelo, Antonello ^b   Babitt, Jodie L ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

BONE MORPHOGENETIC PROTEIN 6; HEPCIDIN; IRON; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; SMAD1 PROTEIN; SMAD5 PROTEIN; SMAD7 PROTEIN; SMAD8 PROTEIN; TRANSFERRIN;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; IN VIVO STUDY; IRON OVERLOAD; IRON STORAGE; LIVER; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION; TRANSFERRIN BLOOD LEVEL; WESTERN BLOTTING;

ANIMALS; ANTIMICROBIAL CATIONIC PEPTIDES; BONE MORPHOGENETIC PROTEIN 6; HOMEOSTASIS; IRON; LIVER; MALE; MICE; MICE, INBRED C57BL; MITOGEN-ACTIVATED PROTEIN KINASE 1; MITOGEN-ACTIVATED PROTEIN KINASE 3; MODELS, ANIMAL; SIGNAL TRANSDUCTION; SMAD PROTEINS; TRANSFERRIN;

EID: 79959562083     PISSN: 02709139     EISSN: 15273350     Source Type: Journal    
DOI: 10.1002/hep.24359     Document Type: Article

References (36)

1. Babitt JL, Lin HY. Molecular mechanisms of hepcidin regulation: implications for the anemia of CKD. Am J Kidney Dis 2010; 55: 726-741.
2. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306: 2090-2093.
3. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, 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: 7811-7819.
4. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110: 1037-1044.
5. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003; 101: 2461-2463.
6. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004; 113: 1271-1276.
7. Vecchi C, Montosi G, Zhang K, Lamberti I, Duncan SA, Kaufman RJ, et al. ER stress controls iron metabolism through induction of hepcidin. Science 2009; 325: 877-880.
8. Corradini E, Babitt JL, Lin HY. The RGM/DRAGON family of BMP co-receptors. Cytokine Growth Factor Rev 2009; 20: 389-398.
9. Andriopoulos B Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 2009; 41: 482-487.
10. Mleczko-Sanecka K, Casanovas G, Ragab A, Breitkopf K, Müller A, Boutros M, et al. SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood 2010; 115: 2657-2665.
11. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dubé MP, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004; 36: 77-82.
12. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006; 38: 531-539.
13. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2005; 2: 399-409.
14. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 2009; 41: 478-481
15. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 2007; 117: 1933-1939.
16. Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA, et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 2008; 4: 33-41.
17. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, 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: 1503-1509.
18. Corradini E, Garuti C, Montosi G, Ventura P, Andriopoulos B Jr, Lin HY, et al. Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. Gastroenterology 2009; 137: 1489-1497.
19. 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: 16416-16423.
20. Kautz L, Meynard D, Besson-Fournier C, Darnaud V, Al Saati T, Coppin H, et al. BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood 2009; 114: 2515-2520.
21. Wallace DF, Summerville L, Crampton EM, Frazer DM, Anderson GJ, Subramaniam VN. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. HEPATOLOGY 2009; 50: 1992-2000.
22. Corradini E, Schmidt PJ, Meynard D, Garuti C, Montosi G, Chen S, et al. BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology 2010; 139: 1721-1729.
23. Ryan JD, Ryan E, Fabre A, Lawless MW, Crowe J. Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis. HEPATOLOGY 2010; 52: 1266-1273.
24. Bolondi G, Garuti C, Corradini E, Zoller H, Vogel W, Finkenstedt A, et al. Altered hepatic BMP signaling pathway in human HFE hemochromatosis. Blood Cells Mol Dis 2010; 45: 308-312.
25. 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: 765-772.
26. Calzolari A, Raggi C, Deaglio S, Sposi NM, Stafsnes M, Fecchi K, 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: 4486-4498
27. Poli M, Luscieti S, Gandini V, Maccarinelli F, Finazzi D, Silvestri L, et al. Transferrin receptor 2 and HFE regulate furin expression via MAPK/Erk signalling. Implications for transferrin-dependent hepcidin regulation. Haematologica 2010; 95: 1832-1840.
28. Guo X, Wang XF. Signaling cross-talk between TGF-β/BMP and other pathways. Cell Res 2009; 19: 71-88.
29. Arndt S, Maegdefrau U, Dorn C, Schardt K, Hellerbrand C, Bosserhoff AK. Iron-induced expression of bone morphogenic protein 6 in intestinal cells is the main regulator of hepatic hepcidin expression in vivo. Gastroenterology 2010; 138: 372-382.
30. Kautz L, Besson C, Meynard D, Latour C, Roth MP, Coppin H. Iron overload induces Bmp6 expression in the liver but not in the duodenum. Haematologica 2011; 96: 199-203.
31. Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Purdie DM, Crawford DH, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 2003; 361: 669-673.
32. Détivaud L, Nemeth E, Boudjema K, Turlin B, Troadec MB, Leroyer P, et al. Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function. Blood 2005; 106: 746-748.
33. Lin L, Valore EV, Nemeth E, Goodnough JB, Gabayan V, Ganz T. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood 2007; 110: 2182-2189.
34. Le Lan C, Loréal O, Cohen T, Ropert M, Glickstein H, Lainé F, et al. Redox active plasma iron in C282Y/C282Y hemochromatosis. Blood 2005; 105: 4527-4531.
35. 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: 502-511.
36. Piperno A, Girelli D, Nemeth E, Trombini P, Bozzini C, Poggiali E, et al. Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Blood 2007; 110: 4096-4100.