Erythroferrone exacerbates iron overload and ineffective extramedullary erythropoiesis in a mouse model of β-thalassemia.

β-thalassemia is characterized by chronic hepcidin suppression and iron overload, even in patients who are not transfused. The HbbTh3/+ (Th3/+) mouse model of non-transfusion-dependent β-thalassemia (NTDBT) partially recapitulates the human phenotype but lacks chronic hepcidin suppression, progressive iron accumulation into adulthood, or the interindividual variation of the rate of iron loading seen in patients. Erythroferrone (ERFE) is an erythroid regulator that suppresses hepcidin during increased erythropoiesis. ERFE concentrations in the sera of NTDBT patients correlate negatively with hepcidin but vary over a broad range, possibly explaining the variability of iron overload in patients. To analyze the effect of high ERFE concentrations on hepcidin and iron overload in NTDBT, we crossed Th3/+ mice with erythroid ERFE-overexpressing transgenic mice. Th3/ERFE transgenic mice suffered high perinatal mortality but embryos at E18.5 showed similar viability, appearance and anemia as Th3/+ mice. Compared to Th3/+ littermates, adult Th3/ERFE mice had similarly severe anemia, but manifested greater suppression of serum hepcidin, and increased iron accumulation in liver, kidney, and spleen. The Th3/ERFE mice had much higher concentrations of serum ERFE than either parental strain, a finding attributable to both higher number of erythroblasts and higher production of ERFE by each erythroblast.Th3/+ and Th3/ERFE mice had similar RBC count and shortened erythrocyte lifespan but Th3/ERFE mice had increased number of erythroid precursors in their larger spleens, indicative of worse ineffective extramedullary erythropoiesis. Thus high ERFE concentrations increase the severity of non-transfusional iron overload and ineffective erythropoiesis in thalassemic mice but do not substantially affect anemia or hemolysis.