Paracrine Bone Morphogenetic Protein Signaling in Iron Homeostasis

Iron is an essential nutrient that is required not only for hemoglobin production in red blood cells, but also as a co-factor of many other proteins that perform fundamental cellular processes. However, excess iron can generate free oxygen radicals that can be toxic. Cells and organisms have therefore evolved mechanisms to tightly control iron levels. Systemic iron homeostasis is governed by the iron hormone hepcidin that binds and degrades the iron exporter ferroportin to limit iron absorption from dietary sources and iron release from iron-recycling macrophages and hepatocyte stores. The key source of hepcidin that controls systemic iron homeostasis is the liver. Hepcidin production by the liver is coordinated by several signals that communicate the body's iron needs. Increases in serum and tissue iron induce hepcidin production, whereas iron deficiency suppresses hepcidin production, as feedback mechanisms to maintain steady state iron levels. Inflammation induces hepcidin to limit iron availability to infectious organisms that also require iron to grow and proliferate. Increases in erythropoietic drive suppress hepcidin production to increase iron availability for red blood cell production. The bone morphogenetic protein (BMP) signaling pathway is the central signal transduction pathway that controls hepcidin production in the liver. Activation of BMP signaling by iron loading or suppression of BMP signaling by iron deficiency or erythropoietic drive are key mechanisms by which these signals control hepcidin transcription. Iron loading increases production of BMP6 and BMP2 ligands by liver endothelial cells. Endothelial-derived BMP6 and BMP2 have paracrine actions on BMP receptors and the co-receptor hemojuvelin on hepatocytes to phosphorylate SMAD transcription factors, which translocate to the nucleus to regulate hepcidin transcription. Erythropoietic drive increases the production of erythroferrone by erythrocyte precursors. Erythroferrone is secreted into the circulation where it binds BMP ligands to prevent their interaction with cell surface receptors, thereby inhibiting hepcidin transcription. This talk will focus on recent insights into the molecular mechanisms by whch paracrine BMP signaling in the liver coordinates hepcidin production to regulate systemic iron homeostasis.