BMP6 is a Key Endogenous Regulator of Hepcidin Expression and Iron Metabolism

Overview

Journal Nat Genet

Specialty Genetics

Date 2009 Mar 3

PMID 19252486

Citations 371

Authors

Billy Andriopoulos Jr

Elena Corradini

Yin Xia

Sarah A Faasse

Shanzhuo Chen

Lovorka Grgurevic

Mitchell D Knutson

Antonello Pietrangelo

Slobodan Vukicevic

Herbert Y Lin

Jodie L Babitt

Affiliations

Soon will be listed here.

Abstract

Juvenile hemochromatosis is an iron-overload disorder caused by mutations in the genes encoding the major iron regulatory hormone hepcidin (HAMP) and hemojuvelin (HFE2). We have previously shown that hemojuvelin is a co-receptor for bone morphogenetic proteins (BMPs) and that BMP signals regulate hepcidin expression and iron metabolism. However, the endogenous BMP regulator(s) of hepcidin in vivo is unknown. Here we show that compared with soluble hemojuvelin (HJV.Fc), the homologous DRAGON.Fc is a more potent inhibitor of BMP2 or BMP4 but a less potent inhibitor of BMP6 in vitro. In vivo, HJV.Fc or a neutralizing antibody to BMP6 inhibits hepcidin expression and increases serum iron, whereas DRAGON.Fc has no effect. Notably, Bmp6-null mice have a phenotype resembling hereditary hemochromatosis, with reduced hepcidin expression and tissue iron overload. Finally, we demonstrate a physical interaction between HJV.Fc and BMP6, and we show that BMP6 increases hepcidin expression and reduces serum iron in mice. These data support a key role for BMP6 as a ligand for hemojuvelin and an endogenous regulator of hepcidin expression and iron metabolism in vivo.

Citing Articles

Green forage impacts on the DNA methylation in the ruminal wall of Italian mediterranean dairy buffaloes.

Fioriniello S, Salzano A, Bifulco G, Aiese Cigliano R, Della Ragione F, Campanile G Sci Rep. 2025; 15(1):8074.

PMID: 40057542 PMC: 11890600. DOI: 10.1038/s41598-025-91969-y.

BMP6 participates in the molecular mechanisms involved in APAP hepatotoxicity.

Maranon P, Isaza S, Rey E, Rada P, Garcia-Garcia Y, Dear J Arch Toxicol. 2025; 99(3):1187-1202.

PMID: 39827450 PMC: 11821676. DOI: 10.1007/s00204-024-03954-5.

Transcriptomic Response of the Ovarian Follicle Complex in Post-Vitellogenic Rainbow Trout to 17α,20β-Dihdroxy-4-pregnen-3-one In Vitro.

Ma H, Gao G, Palti Y, Tripathi V, Birkett J, Weber G Int J Mol Sci. 2024; 25(23).

PMID: 39684392 PMC: 11640809. DOI: 10.3390/ijms252312683.

Repulsive guidance molecules b (RGMb): molecular mechanism, function and role in diseases.

Zhang J, Jiang Y, Zhang Z, Li S, Fan H, Gu J Expert Rev Mol Med. 2024; 26:e24.

PMID: 39375839 PMC: 11488336. DOI: 10.1017/erm.2024.24.

The prodomain of bone morphogenetic protein 2 promotes dimerization and cleavage of BMP6 homodimers and BMP2/6 heterodimers.

Chauhan P, Xue Y, Kim H, Fisher A, Babitt J, Christian J J Biol Chem. 2024; 300(10):107790.

PMID: 39303917 PMC: 11735993. DOI: 10.1016/j.jbc.2024.107790.

References

Nemeth E, Valore E, Territo M, Schiller G, Lichtenstein A, Ganz T . Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2002; 101(7):2461-3. DOI: 10.1182/blood-2002-10-3235. View

Yu P, Hong C, Sachidanandan C, Babitt J, Deng D, Hoyng S . Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 2007; 4(1):33-41. PMC: 2727650. DOI: 10.1038/nchembio.2007.54. View

Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J . Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2002; 33(1):21-2. DOI: 10.1038/ng1053. View

Verga Falzacappa M, Casanovas G, Hentze M, Muckenthaler M . A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J Mol Med (Berl). 2008; 86(5):531-40. DOI: 10.1007/s00109-008-0313-7. View

Nicolas G, Chauvet C, Viatte L, Danan J, Bigard X, Devaux I . The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002; 110(7):1037-44. PMC: 151151. DOI: 10.1172/JCI15686. View

Andrews N . Forging a field: the golden age of iron biology. Blood. 2008; 112(2):219-30. PMC: 2442739. DOI: 10.1182/blood-2007-12-077388. View

Solloway M, Dudley A, Bikoff E, Lyons K, Hogan B, Robertson E . Mice lacking Bmp6 function. Dev Genet. 1998; 22(4):321-39. DOI: 10.1002/(SICI)1520-6408(1998)22:4<321::AID-DVG3>3.0.CO;2-8. View

Wang R, Li C, Xu X, Zheng Y, Xiao C, Zerfas P . A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005; 2(6):399-409. DOI: 10.1016/j.cmet.2005.10.010. View

Gehrke S, Kulaksiz H, Herrmann T, Riedel H, Bents K, Veltkamp C . Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron. Blood. 2003; 102(1):371-6. DOI: 10.1182/blood-2002-11-3610. View

10.

Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen B . IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004; 113(9):1271-6. PMC: 398432. DOI: 10.1172/JCI20945. View

11.

Simic P, Buljan Culej J, Orlic I, Grgurevic L, Draca N, Spaventi R . Systemically administered bone morphogenetic protein-6 restores bone in aged ovariectomized rats by increasing bone formation and suppressing bone resorption. J Biol Chem. 2006; 281(35):25509-21. DOI: 10.1074/jbc.M513276200. View

12.

Huang F, Pinkus J, Pinkus G, Fleming M, Andrews N . A mouse model of juvenile hemochromatosis. J Clin Invest. 2005; 115(8):2187-91. PMC: 1180543. DOI: 10.1172/JCI25049. View

13.

Pietrangelo A . Hereditary hemochromatosis. Biochim Biophys Acta. 2006; 1763(7):700-10. DOI: 10.1016/j.bbamcr.2006.05.013. View

14.

Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang R . Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood. 2008; 112(4):1503-9. DOI: 10.1182/blood-2008-03-143354. View

15.

Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P . A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2000; 276(11):7811-9. DOI: 10.1074/jbc.M008923200. View

16.

Babitt J, Huang F, Wrighting D, Xia Y, Sidis Y, Samad T . Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006; 38(5):531-9. DOI: 10.1038/ng1777. View

17.

Babitt J, Zhang Y, Samad T, Xia Y, Tang J, Campagna J . Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J Biol Chem. 2005; 280(33):29820-7. DOI: 10.1074/jbc.M503511200. View

18.

Shi Y, Massague J . Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003; 113(6):685-700. DOI: 10.1016/s0092-8674(03)00432-x. View

19.

Samad T, Rebbapragada A, Bell E, Zhang Y, Sidis Y, Jeong S . DRAGON, a bone morphogenetic protein co-receptor. J Biol Chem. 2005; 280(14):14122-9. DOI: 10.1074/jbc.M410034200. View

20.

Xia Y, Babitt J, Sidis Y, Chung R, Lin H . Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood. 2008; 111(10):5195-204. PMC: 2384142. DOI: 10.1182/blood-2007-09-111567. View