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Erythroferrone: the missing link in β-thalassemia?

Ivan C. Moura and Olivier Hermine

In this issue of Blood, Kautz et al1 show that the ablation of the erythroid-derived factor erythroferrone (ERFE), which has been shown to be highly expressed in β-thalassemic mice,2 restores hepcidin levels and corrects iron overload. However, correction of hepcidin levels in those mice does not improve anemia of β-thalassemia.

β-Thalassemias are monogenic diseases characterized by the lack or reduction of the hemoglobin β-globin chain expression resulting in an increase of the α/β globin ratio. The excess free α chains aggregate and precipitate in erythroblasts, leading to damage of cell membranes and reactive oxygen species (ROS) generation, leading to ineffective erythropoiesis. Ineffective erythropoiesis is characterized by an expansion of immature erythroblasts associated with apoptosis of mature erythroblasts at the polychromatophilic stage, leading to a major reduction of red cell production.3,4 In addition, ineffective erythropoiesis of β-thalassemia is associated with iron overload.3 Depending on the specific α/β-globin ratio and capacity for fetal hemoglobin synthesis, patients can present at various ends of the phenotype spectrum of biological and clinical severity. Patients with the most severe forms (β-thalassemia major) require chronic red blood cell transfusion for survival and iron chelation to prevent increased plasma iron and formation of non–transferrin-bound iron (NTBI) with its related organ damage (eg, liver, heart, and/or endocrine organs).4

Patients associated with a milder phenotype (β-thalassemia intermedia or non–transfusion-dependent thalassemia) may need only sporadic blood transfusions. However, because of ineffective erythropoiesis, these patients exhibit increased iron absorption and NTBI, leading to severe iron overload, its clinical manifestations, and eventually death. In addition, iron overload may further aggravate ineffective erythropoiesis by stimulating erythroblast ROS production, which increases the α/β-globin chains imbalance. ROS may also stimulate growth differentiation factor 11 (GDF11) expression, a novel actor in ineffective erythropoiesis that causes erythroid expansion of immature erythroblasts and inhibition of end-stage erythroid maturation.5 For the last decade, investigators have focused on understanding the mechanisms underlying iron overload in ineffective erythropoiesis, hypothesizing that correction of ineffective erythropoiesis would significantly reduce iron overload and improve anemia, ultimately increasing overall survival of patients with β-thalassemia.

Hepcidin, a small peptide mainly produced by the liver, is absolutely required for the maintenance of systemic iron homeostasis in basal conditions.6 Hepcidin controls serum iron levels by binding to ferroportin (FPN), the only known iron exporter, and inducing its degradation. Low hepcidin stabilizes FPN at the cellular membrane, promoting dietary iron absorption in the duodenum, increasing the release of iron from macrophages following erythrophagocytosis, and enabling iron mobilization from hepatocytes. Likewise, hepcidin is suppressed in conditions associated with accelerated erythropoiesis (eg, anemia due to bleeding, hemolysis, or iron deficiency) and ineffective erythropoiesis (eg, β-thalassemia).

Two members of the transforming growth factor-β superfamily, GDF15 and twisted gastrulation,7,8 have been proposed as pathologic suppressors of hepcidin in ineffective erythropoiesis, but several experimental and in vivo data in human favor at most a minor role for all these factors in iron overload in ineffective erythropoiesis. In contrast, the Ganz laboratory has shown that ERFE, a member of the C1q-tumor necrosis factor–related family of proteins, is the major negative regulator of hepcidin in conditions of stress or ineffective erythropoiesis.2 ERFE is produced by erythroid precursors in the bone marrow on erythropoietin (EPO) stimulation and represses liver hepcidin production by a still unknown mechanism.

ERFE is probably not the sole erythroid regulator of hepcidin because adult Erfe-deficient mice had normal hematologic and iron parameters. Kautz et al1 elegantly show that ERFE messenger RNA levels were remarkably elevated in the bone marrow and the spleen of a mouse model of β-thalassemia intermedia and that ablation of ERFE in thalassemic mice restores hepcidin levels to normal and significantly reduced the liver iron content and serum iron concentration compared with the thalassemic mice, demonstrating that ERFE could be a pathologic suppressor of hepcidin in ineffective erythropoiesis. This work raises the question whether ERFE is the major factor involved in iron overload in ineffective erythropoiesis in humans. This is likely the case because ex vivo studies confirm that EPO induces ERFE in human erythroid precursors. However, no assay is yet available in human serum to assess its value in patients with thalassemia.

Considering the central role of hepcidin in iron regulation, it is not surprising that hepcidin has become a promising target for increasing its expression in anemia associated with ineffective erythropoiesis and iron overload. In mouse models of β-thalassemia, a moderate increase in hepcidin, caused either by transgenic hepcidin overexpression, knockdown of the negative hepcidin regulator matriptase, or administration of hepcidin agonists, resulted not only in reducing iron overload but also in improvement in anemia.9 This effect results in decreased α-globin precipitation, lower ROS, apoptosis, and GDF11 in erythroid precursors.

Surprisingly, although ERFE deficiency in β-thalassemic mice improves iron overload, anemia is not improved, suggesting that hepcidin may play additional roles locally in the bone marrow or ERFE may have an auto/paracrine role preventing erythroid maturation. Interestingly, inhibition of GDF11 in β-thalassemia results in correction of iron overload. Currently, there is no evidence showing that GDF11 directly regulates iron homeostasis, but it would be interesting to investigate its role in ERFE production and conversely the role of ERFE in GDF11 expression at the erythroblast level.

Understanding coregulation of erythropoiesis and iron metabolism remains an active field of investigation. The recently described ERFE is a novel regulator with its full array of functions and mechanism of action still to be determined both in normal and pathologic erythropoiesis. In addition, the ERFE/hepcidin pathway may play a role in iron homeostasis in various tissues including the heart and the brain, in which its disturbance may lead to tissue damage. A further understanding of this pathway may serve to inform more precise targets for medical intervention to correct iron overload in β-thalassemias, possibly other anemia associated with ineffective erythropoiesis (eg, myelodysplastic syndromes and congenital anemia), and possibly primary iron overload disorders.

Footnotes

  • Conflict-of-interest disclosure: The authors declare no competing financial interests.

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