An update on iron homeostasis: make new friends, but keep the old.

A classic Girl Scout song says, "Make new friends/but keep the old/One is silver/and the other gold." This review focuses on the past decade of discovery in the field of iron homeostasis, which has identified "new friends" or key modifiers of the critical systemic iron regulator, hepcidin antimicrobial peptide. The foundation for these discoveries has been the identification of mutated genes in well-characterized cohorts of patients with inherited hemochromatosis from across the globe. Transgenic mouse models of iron overload and iron-restricted anemia have also contributed to understanding molecular pathophysiology in ways that could never be accomplished in human subjects alone. The majority of these newly discovered molecules coordinate signaling through the bone morphogenetic protein pathway of ligands, receptors and coreceptors, intracellular signaling and transcription. The discovery of these proteins and their interactions with "old friends," such as the 1st known hereditary hemochromatosis gene product, HFE and transferrin receptor, has opened the field of iron homeostasis to include regulatory networks involving signal transduction pathways, in particular, the mitogen-activated protein kinase and Smad pathways. These newly discovered partnerships have also made way for opportunities to develop novel therapeutics for the treatment of iron regulatory disorders, including hemochromatosis.