Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice

Summary

Erythroferrone, a glycoprotein hormone produced by erythroid cells in response to hemorrhage, hypoxia or other erythropoietic stimuli, suppresses the hepatic production of the iron-regulatory hormone hepcidin and thereby mobilizes iron for erythropoiesis. Erythroferrone is thought to interfere with paracrine BMP signaling that regulates hepcidin transcription in hepatocytes. Erythroferrone is pathologically overproduced in anemias with ineffective erythropoiesis but its contribution to the clinical manifestations of these anemias is not well understood. We generated three lines of transgenic mice with graded erythroid overexpression of erythroferrone and showed that they developed dose-dependent iron overload, impaired hepatic BMP signaling and relative hepcidin deficiency. At the highest levels of erythroferrone overexpression the mice manifested decreased perinatal survival, impaired growth, small hypofunctional kidneys, decreased gonadal fat depots and neurobehavioral abnormalities, all consistent with impaired organ-specific BMP signaling during development. Neutralizing excessive erythroferrone in congenital anemias with ineffective erythropoiesis may not only prevent iron overload but may have additional benefits for growth and development.