Bone morphogenetic proteins as regulators of iron metabolism

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-β) superfamily of signaling molecules. In addition to protean roles in embryonic development, germ-line specification, and cellular differentiation, a central role in iron homeostasis has recently been demonstrated for certain BMPs. Specifically, BMP6 serves to relate hepatic iron stores to the hepatocellular expression of the iron-regulatory hormone hepcidin. This regulation occurs via cellular SMAD-signaling molecules and is strongly modulated by the BMP coreceptor hemojuvelin (HJV). Mutations in certain genes influencing signaling to hepcidin via the BMP/SMAD pathway are associated with human disorders of iron metabolism, such as hereditary hemochromatosis and iron-refractory iron-deficiency anemia. Evidence suggests that signals in addition to iron stores influence hepcidin expression via the BMP/SMAD pathway. This review summarizes the details of BMP/SMAD signaling, with a particular focus on its role in iron homeostasis and iron-related diseases.