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Hepcidin expression decreased by recombinant erythroferrone
NEW ORLEANS — An erythroid factor that represses hepcidin during increased erythropoietic activity may contribute to the pathogenesis of iron-loading anemias, including beta-thalassemia, according to study findings presented at the ASH Annual Meeting and Exhibition.
“We identified a new protein that may be the erythroid regulator described a few decades ago,” Leon Kautz, MD, PhD, of the University of California at Los Angeles, told HemOnc Today. “We show that erythroferrone is the erythroid factor coordinating iron supply for erythropoiesis. Erfe functions by suppressing the production of the iron-regulatory hormone hepcidin. However, further work is required to definitely answer whether Erfe is ‘the’ erythroid regulator or ‘an’ erythroid regulator.”
Leon Kautz
Kautz and colleagues tested the hepcidin mRNA response to hemorrhage in wild-type mice and in mice without hemojuvelin or TfR2. They found that hemojuvelin and TfR2 are not essential for hepcidin mRNA response.
The researchers then initiated an unbiased analysis to identify potential suppressors of hepcidin by assessing the time course of bone marrow response to hemorrhage utilizing gene chip-based expression profiling.
Less than 12 erythroid-specific transcripts were identified that changed before the suppression of hepcidin mRNA. Researchers characterized the previously unidentified transcript as “erythroferrone.”
After phlebotomy or EPO stimulation and preceding hepcidin suppression, erythroferrone mRNA expression was significantly increased in the bone marrow and the spleen 4h.
Mice without erythroferrone did not suppress hepcidin mRNA after phlebotomy or EPO injection and recovered more slowly from phlebotomy-induced anemia compared with their wild-type counterparts.
No significant defects in baseline erythropoiesis, nor the composition or maturation of erythroid precursors, were found. That suggests erythroferrone exerts its effect specifically on hepcidin for the regulation of iron availability, according to the researchers.
“If the contribution of ERFE to hepcidin suppression and iron overload in iron-loading anemias (eg, beta-thalassemia and congenital dyserythropoietic anemia) is confirmed in clinical studies, ErFe neutralization would be a rational and apparently specific therapeutic strategy for these diseases,” Kautz said. “At the other end of the disease spectrum, the ability of ErFe to suppress hepcidin could be useful in the treatment of iron-restrictive anemias characterized by increased hepcidin, including anemia of inflammation, anemia of chronic kidney diseases and iron-refractory iron-deficiency anemia.”
For more information:
Kautz L. Abstract #4. Presented at: ASH Annual Meeting and Exhibition; Dec. 7-10, 2013; New Orleans.
Disclosure: The researchers report no relevant financial disclosures.
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This work provides the first description of a long-sought-after hormone that is produced in the bone marrow in response to hemorrhage or erythropoietin (EPO) administration. This hormone, which the authors named erythroferrone, acts by increasing the body’s absorption of iron in the gut. To do this, erythroferrone greatly dampens liver expression of hepcidin, a small peptide that reduces iron absorption in the gut by inducing the degradation of iron transporters.
Scientifically, this work illuminates a mechanism by which the marrow responds to blood loss to increase production of red blood cells, which require a tremendous amount of iron for their production. It also opens the opportunity for dissection of the precise mechanisms by which erythroferrone is induced by blood loss, for determining which are the key domains of the protein hormone involved in its actions, and for learning how erythroferrone acts on the liver to depress hepcidin synthesis, including the identification of a hepatic erythroferrone receptor. Understanding each of these steps will provide targets for new drugs that can be designed to either increase or suppress iron absorption.
One of the important insights produced by this work was the fact that erythroferrone levels are greatly elevated in the blood of thalassemic mice, a finding that will almost certainly also apply to humans with thalassemia. This immediately opens up the possibility that by blocking production of erythroferrone in the bone marrow or its actions on the liver, it will be possible to reduce iron absorption in patients with thalassemia. These patients often suffer iron-mediated damage to organs, including the liver, heart, pancreas, and endocrine system. Current therapies for iron overload in thalassemia require administration of iron chelators for up to 12 hours per day, 5 to 7 days per week. Erythroferrone itself potentially could be used to treat rare anemias where the absorption of iron is inadequate to keep up with erythropoietic need, or for the treatment of anemia of inflammation, which is characterized by high hepcidin levels.
I thought the method for identifying erythroferrone was quite ingenious. The investigators knew that the hormone produced in the bone marrow would have to be produced ahead of the drop in hepcidin transcription. They therefore carried out mRNA expression profiling of bone marrow after phlebotomy or EPO administration and identified only a handful of transcripts that increased in expression before the drop in hepcidin mRNA expression. They focused on erythroferrone because its putative structure — derived from translation of the mRNA — predicted a secreted protein, a requirement for a bone marrow hormone whose primary effect is on the liver.
There are many possibilities for where to go with these findings. As with most new discoveries, the discovery of erythroferrone opens up many new questions that will have to be answered. I think obvious areas to explore are finding ways to prevent erythroferrone production or to block its effect on the liver (eg, identifying its receptor) as first steps in treating iron overload.