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BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism

Nature Genetics volume 41, pages 482–487 (2009)Cite this article

Abstract

Juvenile hemochromatosis is an iron-overload disorder caused by mutations in the genes encoding the major iron regulatory hormone hepcidin (HAMP)1 and hemojuvelin (HFE2)2. We have previously shown that hemojuvelin is a co-receptor for bone morphogenetic proteins (BMPs) and that BMP signals regulate hepcidin expression and iron metabolism3,4. 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.

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Figure 1: DRAGON.Fc selectively inhibits BMP induction of hepcidin expression in vitro but does not affect hepcidin expression or iron metabolism in vivo.
Figure 2: Neutralizing BMP6 inhibits hepatic hepcidin expression and increases serum iron and transferrin saturation in vivo.
Figure 3: Bmp6-null mice show reduced hepatic hepcidin expression, increased spleen ferroportin expression, increased serum iron and transferrin saturation, increased liver, heart, and pancreas iron content, and reduced spleen iron content.
Figure 4: BMP6 interacts with HJV.Fc.
Figure 5: BMP6 administration in mice increases Hamp (hepcidin) mRNA expression and reduces serum iron.

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Acknowledgements

We thank V. Rosen for kindly providing BMP2 for our study. We thank L.M. Russo for assistance with animal work. E.C. was supported in part by the Associazione Modenese per le Malattie del Fegato. S.V. was supported in part by the Croatian Ministry of Science, Education, and Sport. H.Y.L. was supported in part by US National Institutes of Health grants RO1 DK-69533 and RO1 DK-071837. J.L.B. was supported in part by National Institutes of Health grant K08 DK-075846 and by a Claflin Distinguished Scholar Award from the Massachusetts General Hospital.

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Author notes

  1. Billy Andriopoulos Jr, Elena Corradini and Yin Xia: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Billy Andriopoulos Jr, Elena Corradini, Yin Xia, Sarah A Faasse, Shanzhuo Chen, Herbert Y Lin & Jodie L Babitt

  2. Center for Hemochromatosis, University Hospital of Modena and Reggio Emilia, Modena, Italy

    Elena Corradini & Antonello Pietrangelo

  3. Laboratory of Mineralized Tissues, School of Medicine, University of Zagreb, Zagreb, Croatia

    Lovorka Grgurevic & Slobodan Vukicevic

  4. Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida, USA

    Mitchell D Knutson

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Contributions

B.A., E.C., Y.X., H.Y.L. and J.L.B. designed experiments. B.A., E.C., Y.X., S.A.F., S.C., L.G. and J.L.B. performed experiments. B.A., E.C., Y.X., S.A.F. and J.L.B. analyzed data. M.D.K., A.P., S.V. and H.Y.L. contributed vital resources and reagents. B.A., E.C., Y.X., A.P., S.V., H.Y.L. and J.L.B. wrote or edited the paper. J.L.B. conceived and oversaw the entire project.

Corresponding author

Correspondence to Jodie L Babitt.

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Competing interests

J.L.B. and H.Y.L. have ownership interest in Ferrumax Pharmaceuticals, which has licensed technology from the Massachusetts General Hospital based on the work described here and in prior publications. Patent applications entitled “Methods and Composition to Regulate Iron Metabolism” and “Methods and Compositions for Regulating Iron Homeostasis by Modulation of BMP6” have been submitted by the Massachusetts General Hospital. S.V. is a Scientific Advisory Board member for Pfizer, Inc. and receives research funding from Genzyme Corp.

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Supplementary Figures 1–7 and Supplementary Table 1 (PDF 4994 kb)

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Andriopoulos Jr, B., Corradini, E., Xia, Y. et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 41, 482–487 (2009). https://doi.org/10.1038/ng.335

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