Identification of erythroferrone as an erythroid regulator of iron metabolism

Kautz, Léon; Jung, Grace; Valore, Erika V.; Rivella, Stefano; Nemeth, Elizabeta; Ganz, Tomas

doi:10.1038/ng.2996

Cited by 936 publications

(1,086 citation statements)

References 43 publications

(56 reference statements)

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“…Elevations in ERFE levels suppress hepcidin‐25 synthesis of the liver to allow iron acquisition from absorption and storage sites, favoring recovery from anemia secondary to blood loss. ERFE knockout mice have normal hematological parameters, but are unable to suppress hepcidin after phlebotomy or EPO injection 1. As a result, ERFE deficient mice have a slower recovery after blood loss.…”

Section: Tablementioning

confidence: 99%

“…We anticipated this 100‐fold dilution would allow the measurement of ERFE levels since the measurement range of the kit is given as 15.6‐1000 pg/mL and concentrations observed in a mouse model of β‐thalassemia intermedia were 10‐25 ng/mL 1. For blood donors, we also included dilutions of 2‐ to 10‐fold based on the assumption that pre‐donation values would be <100 pg/mL as observed for wild‐type mice,1 with a reported 30‐fold increase upon phlebotomy 2b

−0 = measurement at baseline, before donation, −4 = measurement at day 4.

dil, dilutions; NA, not available; ND, not determined; LLOD, lower limit of detection as reported in kit manual: 3.9 pg/mL; sTfR, soluble transferrin receptor.

…”

Section: Tablementioning

confidence: 99%

Section: Tablementioning

confidence: 99%

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EPO and hepcidin plasma concentrations in blood donors and β‐thalassemia intermedia are not related to commercially tested plasma ERFE concentrations

Schotten

et al. 2017

American J Hematol

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Section: Tablementioning

confidence: 99%

−0 = measurement at baseline, before donation, −4 = measurement at day 4.

dil, dilutions; NA, not available; ND, not determined; LLOD, lower limit of detection as reported in kit manual: 3.9 pg/mL; sTfR, soluble transferrin receptor.

…”

Section: Tablementioning

confidence: 99%

Section: Tablementioning

confidence: 99%

See 1 more Smart Citation

EPO and hepcidin plasma concentrations in blood donors and β‐thalassemia intermedia are not related to commercially tested plasma ERFE concentrations

Schotten

et al. 2017

American J Hematol

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“…Two members of the transforming growth factor-β superfamily, growth differentiation factor 15 (GDF15) and twisted gastrulation (TWSG1), have been previously recognized as pathological suppressors of hepcidin in ineffective erythropoiesis [13,14]. Additionally, a recently identified erythroid hormone erythroferrone (ERFE) was demonstrated to conduct a suppression of hepcidin at the early stage after endogenous or exotic erythropoietic stimulation [15]. ERFE ablation resulted in a more severe anemia with inappropriately elevated hepcidin expression in heat-killed Brucella abortus-induced inflammation anemia [16].…”

Section: Introductionmentioning

confidence: 99%

EPO-dependent induction of erythroferrone drives hepcidin suppression and systematic iron absorption under phenylhydrazine-induced hemolytic anemia

Jiang

Gao

Chen

et al. 2016

Blood Cells, Molecules, and Diseases

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a b s t r a c t a r t i c l e i n f oHemolytic anemia is a common form of anemia due to hemolysis, resulting in disordered iron homeostasis. In this study, a dose of 40 mg/kg phenylhydrazine (PHZ) was injected into mice to successfully establish a pronounced anemia animal model, which resulted in stress erythropoiesis and iron absorption. We found that serum erythropoietin (EPO) concentration was dramatically elevated by nearly 5000-fold for the first 2 days, and then drop to the basal level on day 6 after PHZ injection. Mirrored with serum EPO concentration, the mRNA expression of erythroferrone (ERFE) was rapidly increased in the bone marrow and spleen 3 days after injection of PHZ, and then gradually decreased but was still higher than baseline on day 6. In addition, we also found that the hepcidin mRNA levels were gradually reduced almost up to 8-fold on day 5, and then was ameliorated compared to the untreated control. Mechanistic investigation manifested that the increase of serum EPO essentially determined the induction of ERFE expression particular at the first 3 days after PHZ treatment. Lentiviral mediated ERFE knockdown significantly restrained hepcidin suppression under PHZ treatment. Thus, our data unearthed EPOdependent ERFE expression acts as an erythropoiesis-driven regulator of iron metabolism under PHZ-induced hemolytic anemia.

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“…Although the exact molecular details of this regulation are not well understood, it is believed that the erythroid compartment releases a soluble factor which limits the production of Hamp in the liver [4]. Several candidate regulators including growth differentiation factor 15 (GDF15), twisted gastrulation 1 (TWSG1) and more recently erythroferrone (ERFE) have been reported [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron‐deficient anemia

et al. 2016

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Iron metabolism and erythropoiesis are inherently interlinked physiological processes. Regulation of iron metabolism is mediated by the iron-regulatory hormone hepcidin. Hepcidin limits the amount of iron released into the blood by binding to and causing the internalization of the iron exporter, ferroportin. A number of molecules and physiological stimuli, including erythropoiesis, are known to regulate hepcidin. An increase in erythropoietic demand decreases hepcidin, resulting in increased bioavailable iron in the blood. Transferrin receptor 2 (TFR2) is involved in the systemic regulation of iron metabolism. Patients and mice with mutations in TFR2 develop hemochromatosis due to inappropriate hepcidin levels relative to body iron. Recent studies from our laboratory and others have suggested an additional role for TFR2 in response to iron-restricted erythropoiesis. These studies used mouse models with perturbed systemic iron metabolism: anemic mice lacking matriptase-2 and Tfr2, or bone marrow transplants from iron-loaded Tfr2 null mice. We developed a novel transgenic mouse model which lacks Tfr2 in the hematopoietic compartment, enabling the delineation of the role of Tfr2 in erythroid development without interfering with its role in systemic iron metabolism. We show that in the absence of hematopoietic Tfr2 immature polychromatic erythroblasts accumulate with a concordant reduction in the percentage of mature erythroid cells in the spleen and bone marrow of anemic mice. These results demonstrate that erythroid Tfr2 is essential for an appropriate erythropoietic response in iron-deficient anemia. These findings may be of relevance in clinical situations in which an immediate and efficient erythropoietic response is required.

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Identification of erythroferrone as an erythroid regulator of iron metabolism

Cited by 936 publications

References 43 publications

EPO and hepcidin plasma concentrations in blood donors and β‐thalassemia intermedia are not related to commercially tested plasma ERFE concentrations

EPO and hepcidin plasma concentrations in blood donors and β‐thalassemia intermedia are not related to commercially tested plasma ERFE concentrations

EPO-dependent induction of erythroferrone drives hepcidin suppression and systematic iron absorption under phenylhydrazine-induced hemolytic anemia

Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron‐deficient anemia

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