BMP-6 is a key endogenous regulator of hepcidin expression and iron metabolism

By B. Andriopoulos, E. Corradini, Yin Xia, Sarah A. Faasse, Shanzhuo Chen, L. Grgurević, M. Knutson, A. Pietrangelo, S. Vukicevic, Herbert Y. Lin and 1 more. Nature Genetics, 2009

774 citations recorded by the source corpus.

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.

Subfields: Hematology, Nutrition and Dietetics, Plant Science

View Paper: https://www.semanticscholar.org/paper/8c80bb9deb040f837beb928a9bd5dfd111d3bb69

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In Hematology

1. T. Ganz
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1. T. Ganz

Citations in the corpus

• Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases (2011, background): “Selective inhibition of BMP6 signaling abrogates iron-induced up-regulation of hepcidin.(27) Hemojuvelin is a BMP6 coreceptor, and it facilitates the binding of BMP6 to its receptor; knockout of the HJV gene markedly decreases BMP6 signaling in hepcidin expression and causes iron overload.”
• Systemic iron homeostasis. (2013, background): “BMP6 is the essential and specific BMP receptor ligand for iron-related signaling, at least in mice, as BMP6 knockout mice have very low hepcidin and develop severe iron overload, with no evidence of any other abnormalities (6, 153).”