Erythropoietic regulators of iron metabolism

Abstract

Erythropoiesis is the predominant consumer of iron in humans and other vertebrates. By decreasing the transcription of the gene encoding the iron-regulatory hormone hepcidin, erythropoietic activity stimulates iron absorption, as well as the release of iron from recycling macrophages and from stores in hepatocytes. The main erythroid regulator of hepcidin is erythroferrone (ERFE), synthesized and secreted by erythroblasts in the marrow and extramedullary sites. The production of ERFE is induced by erythropoietin (EPO) and is also proportional to the total number of responsive erythroblasts. ERFE acts on hepatocytes to suppress the production of hepcidin, through an as yet unknown mechanism that involves the bone morphogenetic protein pathway. By suppressing hepcidin, ERFE facilitates iron delivery during stress erythropoiesis but also contributes to iron overload in anemias with ineffective erythropoiesis. Although most of these mechanisms have been defined in mouse models, studies to date indicate that the pathophysiology of ERFE is similar in humans. ERFE antagonists and mimics may prove useful for the prevention and treatment of iron disorders.

Keywords: Anemia; Erythroferrone; Erythropoiesis; Hepcidin; Iron.

Fig 1:

Proposed roles of ERFE in matching iron supply to erythropoietic demand during stress erythropoiesis, such as after acute blood loss or acute hemolysis (left panel), contrasted with the pathological role of ERFE in iron-loading anemias with ineffective erythropoiesis, exemplified by β-thalassemia intermedia (right panel). During the physiological response (left panel), anemia causes increased EPO secretion by the kidneys. Driven by EPO, more erythroblasts enter the erythropoietic differentiation pipeline and EPO-stimulated ERFE secretion increases, lowering hepatic hepcidin production and thereby matching iron supply (from the spleen, liver, and duodenum) to increased erythropoiesis. In anemias with ineffective erythropoiesis (right panel), most erythroblasts do not successfully differentiate into mature erythrocytes, leading to anemia and increased EPO production by the kidneys. ERFE secretion is increased both because of EPO stimulation and because of the large numbers of dead-end but ERFE-secreting erythroblasts. Hepcidin is suppressed and iron is mobilized but erythrocyte production cannot increase and so the additional iron is not utilized. Excess iron saturates transferrin and generates NTBI, which is taken up in the liver and other vital organs, causing tissue injury and organ failure.