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 drive still regulate hepcidin in mice lacking either ligand or both. Here, we utilize mice with an inactivating Bmp5 mutation (Bmp5se), 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 show that Bmp5se mutant mice exhibit hepcidin deficiency at 10 days of age, blunted hepcidin induction to oral iron gavage, and mild liver iron loading when fed a low- or high-iron diet. Loss of 1 or 2 functional Bmp5 alleles also leads to more 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 chronic dietary iron loading. Finally, erythroferrone (ERFE) binds directly to BMP5 and inhibits BMP5 induction of hepcidin in vitro. Whereas erythropoietin (EPO) suppresses hepcidin in Bmp5se mutant mice, EPO fails to suppress hepcidin in double Bmp5 and Bmp6 mutant males. Together, these data demonstrate that BMP5 has a functional role in hepcidin and iron homeostasis regulation, particularly under conditions where BMP6 is limited.