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

Abstract

Jodie Babitt and colleagues report that Bmp6-null mice have a phenotype that resembles hereditary hemochromatosis, with increased serum iron concentration and tissue iron overload. Administration of Bmp6 increases hepcidin expression and reduces serum iron, suggesting that Bmp6 is a key endogenous regulator or iron metabolism in vivo 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.