Identity of 'Erythroid Regulator' of Iron Absorption Revealed?

Our understanding of the regulation of iron homeostasis has been greatly facilitated by the discovery of the iron-regulatory protein hepcidin. This small peptide regulates cellular iron export by binding and triggering internalization and degradation of the iron export protein ferroportin. This alters the availability of iron by shifting the serum iron away from erythropoiesis to macrophages and by inhibiting iron absorption by the duodenum.¹  As such, an understanding of the regulation of hepcidin has been central to the pathophysiology of anemia of chronic disease (inflammation induces hepcidin expression by the IL-6 pathway) and various types of hemochromatosis (wherein hepcidin is low).²  However, while understanding hepcidin regulation largely clarified its interaction with iron control mechanisms that were coined by a seminal paper of Clem Finch as a "stores regulator," "hypoxia regulator," and "inflammatory regulator," it failed, however, to explain the increased iron absorption seen in thalassemias and sideroblastic anemias. This mysterious crosstalk between hyperactive inefficient erythropoiesis and anemia was termed the "erythroid regulator."³  Interestingly, in some anemic states with hyperactive erythropoiesis, such as in sickle cell disease, hepcidin is not decreased, and clinically significant iron overload is uncommon, while in thalassemia major and intermedia hepcidin is markedly decreased with a tendency to iron overload that is unrelated to red cell transfusions.⁴ 

The study from Jeff Miller’s laboratory is an important step in solving the identity of the erythroid regulator. In their paper, Tanno and colleagues propose that iron overload in ß-thalassemia patients may result from inhibition of hepcidin by high levels of growth differentiations of factor 15 (GDF15), a member of the transforming growth factor-ß (TGFB) superfamily. They followed up on a well-established fact that in patients with ß-thalassemia, hepcidin expression is decreased, speculating that the thalassemic erythroid precursors produce a hepcidin repressor during their hyperactive and largely apoptotic maturation. Based on this hypothesis, the authors examined transcriptional profiles of TGFB members in primary erythroblasts and detected increased expression and secretion of GDF15 during erythroblast maturation in normal controls. The investigators then hypothesized that elevated numbers of apoptotic erythroblasts in patients with thalassemia might produce increased levels of GDF15. Indeed, they report that in some ß-thalassemia patients, serum levels of GDF15 are dramatically increased and that the serum concentration of GDF15 correlated with elevated erythroblast numbers and iron overload in ß-thalassemia. To examine the regulation of hepcidin expression by GDF15, the authors measured hepcidin expression in primary hepatocytes (cells producing hepcidin) that were exposed to the sera with normal and elevated levels of GDF15, and found that hepcidin production was suppressed by high levels of GDF15. Very high levels of GDF15, however, could not completely suppress hepcidin expression. They also noted that depletion of GDF15 significantly increased hepcidin expression in ß-thalassemia serum. These observations suggest that erythroblast-produced GDF15 is involved in the suppression of hepcidin production and thus leads to augmented iron absorption in ß-thalassemia. However, these studies also suggest that GDF15 is not the sole regulator of hepcidin expression by hyperactive erythropoiesis.