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Erythropoiesis, circulating iron and hepcidin
anemia would result in a much larger increase in serum erythroferrone than would occur following a single injec- tion of erythropoietin, allowing the erythroid regulator to overcome the effect of increases in diferric transferrin. In contrast, the current study involves the acute stimulation of erythropoiesis and, as such, any expansion of the ery- throid marrow would be minimal, allowing the stimulat- ing effect of increased diferric transferrin to overcome the inhibitory effect of erythroferrone and prevent any reduc- tion in Hamp1 expression. Such competition between pathways influencing hepcidin production has been reported previously12,38,39 and these studies indicate that it is the strength of each signal, rather than its origin, that dic- tates HAMP expression. It is also possible that, in b-tha- lassemia, the preferential uptake of diferric transferrin by the greatly expanded erythroid precursor mass causes cir- culating diferric transferrin levels to be relatively low despite higher than normal transferrin saturation, and that this might contribute to the observed decrease in hepcidin.
The increase in spleen size following iron injection also suggests that erythropoiesis is iron-restricted shortly after stimulation with erythropoietin, with the additional iron allowing further expansion of the erythroid marrow. This is supported by the observation of decreased Tfr1 expres- sion in the bone marrow in iron-injected animals. Interestingly, a recent study has suggested that there is an erythroferrone-independent role for erythroid cell TFR1 in the regulation of hepcidin production.40 The authors pro- pose that TFR1 on erythroid precursor cells regulates the production of an unknown soluble factor that influences hepcidin expression in the liver. We would suggest that a
novel factor is unnecessary, as alterations in erythroid TFR1 production will rapidly and preferentially influence the levels of circulating diferric transferrin, which will, in turn, affect hepcidin production. Our results also indicate that such a change in diferric transferrin would not neces- sarily result in a significant difference in serum iron levels, and thus could remain undetected in many studies exam- ining the regulation of hepcidin.
In conclusion, we have demonstrated that diferric trans- ferrin levels are transiently decreased following the stimu- lation of erythropoiesis by erythropoietin injection and suggest that this molecule may contribute to the initial inhibition of hepcidin expression that occurs. We also show that, in certain situations, diferric transferrin can overcome the inhibitory effect of erythroferrone to pre- vent hepcidin inhibition. However, this is likely to depend on the strength of the individual signals, with the effect of erythroferrone clearly overcoming increases in diferric transferrin levels at later time points. As the changes in diferric transferrin levels are not always detected by meas- uring serum iron or transferrin saturation, we suggest that studies investigating the regulation of hepcidin would benefit from direct measurements of diferric transferrin.
Acknowledgments
This work was supported by a Project Grant (APP1051764) (GJA and DMF) and a Senior Research Fellowship (GJA) from the National Health and Medical Research Council of Australia, an Australian Government Research Training Program Scholarship (CSGM) and a Top Up Award from the QIMR Berghofer Higher Degrees Committee (CSGM).
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