BMP5 contributes to hepcidin regulation and systemic iron homeostasis in mice

Hepcidin is the master regulator of systemic iron homeostasis. The bone morphogenetic protein (BMP) signaling pathway is a critical regulator of hepcidin expression in response to iron and erythropoietic drive. Although endothelial-derived BMP6 and BMP2 ligands have key functional roles as endogenous hepcidin regulators, both iron and erythropoietic drives still regulate hepcidin in mice lacking either or both ligands. Here, we used mice with an inactivating Bmp5 mutation (Bmp58e), either alone or together with a global or endothelial Bmp6 knockout, to investigate the functional role of BMP5 in hepcidin and systemic iron homeostasis regulation. We showed that Bmp58e-mutant mice exhibit hepcidin deficiency at age 10 days, blunted hepcidin induction in response to oral iron gavage, and mild liver iron loading when fed on a low-or high-iron diet. Loss of 1 or 2 functional Bmp5 alleles also leads to increased iron loading in Bmp6-heterozygous mice and more profound hemochromatosis in global or endothelial Bmp6-knockout mice. Moreover, double Bmp5-and Bmp6-mutant mice fail to induce hepcidin in response to long-term dietary iron loading. Finally, erythroferrone binds directly to BMP5 and inhibits BMP5 induction of hepcidin in vitro. Although erythropoietin suppresses hepcidin in Bmp58e-mutant mice, it fails to suppress hepcidin in double Bmp5- and Bmp6-mutant males. Together, these data demonstrate that BMP5 plays a functional role in hepcidin and iron homeostasis regulation, particularly under conditions in which BMP6 is limited.

Automated summary

This study reveals the important role of BMP5 in hepcidin and systemic iron homeostasis regulation, particularly when BMP6 is limited. Bmp5 mutant mice exhibit hepcidin deficiency and iron loading, and loss of one or two functional Bmp5 alleles leads to more severe hemochromatosis in Bmp6 knockout mice. Furthermore, erythroferrone can directly bind to BMP5 and inhibit its induction of hepcidin.