Initial Change Of Iron Metabolic Flux Prior To Differentiation Of Erythroid Progenitors After Epoetin Beta Pegol (C.E.R.A.) Treatment

Erythropoiesis and iron metabolism are inextricably linked. Developing immature erythroblasts have an extremely high iron requirement, especially during hemoglobin synthesis. Hepcidin, which inhibits iron efflux by binding to iron exporter ferroportin, is suppressed to promote the supply of required iron. Suppression of hepcidin after erythropoiesis-stimulating agent (ESA) treatment is mainly in an indirect manner, especially via erythropoietic activity, but the nature of suppressive mechanism of hepcidin is still unknown. Epoetin beta pegol (C.E.R.A.) is a novel long-acting ESA, which potentially has intensive and continuous effects on reduction of hepcidin. In the present study, we investigated change of iron metabolic flux associated with enhanced erythropoiesis by C.E.R.A. to analyze the mechanism underlying suppression of hepcidin.

Initial change of iron metabolism was analyzed in C57BL/6N mice intravenously treated with 10 μg/kg of C.E.R.A. or vehicle. Hematological indices such as reticulocyte counts and iron indices including serum hepcidin and iron levels were measured. Reticulocyte hemoglobin equivalent (Ret-He) which reflects the iron status of reticulocyte was also determined. Ter119 and transferrin receptor (CD71) expression on bone marrow cells was evaluated by flow cytometry for analysis of the maturation status of bone marrow erythroblasts.

C.E.R.A. suppressed serum hepcidin levels after 9 hours, while serum iron levels were significantly decreased at 9 hours followed by recovery to the control levels at 24 hours. Ter119(+)CD71(high) immature erythroblasts were decreased and CD71 expression levels on the same cells were increased at 9 hours after C.E.R.A. treatment. C.E.R.A. elevated reticulocyte counts and Ret-He levels at 48 hours.

Transient decrease in serum iron levels and continuous suppression of serum hepcidin levels were observed in early phase after C.E.R.A. treatment, prior to increase in erythroblasts through proliferation and differentiation of erythroid progenitors. Furthermore, considering decrease in immature erythroblasts followed by increase in hemoglobin-rich reticulocytes, it is possible that initial change of iron metabolic flux occurred by the accelerated iron incorporation into immature erythroblasts through CD71 recycling after C.E.R.A. treatment. These results suggest that sensing initial change of iron metabolic flux leads to suppression of hepcidin after C.E.R.A. treatment, but further analysis is needed for the mechanism of increase in iron absorption into immature erythroblasts immediately after C.E.R.A. treatment independent of differentiation of erythroid progenitors.

No relevant conflicts of interest to declare.