RED CELLS, IRON, AND ERYTHROPOIESIS Perturbation of hepcidin expression by BMP type I receptor deletion induces iron

Bone morphogenetic protein (BMP) sig-naling induces hepatic expression of the peptide hormone hepcidin. Hepcidin re-duces serum iron levels by promoting degradation of the iron exporter ferropor-tin. A relative deficiency of hepcidin under-lies the pathophysiology of many of the genetically distinct iron overload disor-ders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin lev-els, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are ex-pressed in murine hepatocytes. We re-port that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3- than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete abla-tion of basal BMP signaling and hepci-din expression. Both Alk2 and Alk3 were required for induction of hepcidin gene expression by BMP2 in cultured hepato-cytes or by iron challenge in vivo. These observations demonstrate that one type I BMP receptor, Alk3, is critically respon-sible for basal hepcidin expression, whereas 2 type I BMP receptors, Alk2 and Alk3, are required for regulation of hepcidin gene expression in response to iron and BMP signaling. (Blood. 2011; 118(15):4224-4230