Статті в журналах: "ERFE"

1

Kautz, Leon, Grace Jung, Elizabeta Nemeth, and Tomas Ganz. "Role of Erythroferrone in the Pathophysiology of Common Anemias." Blood 124, no. 21 (December 6, 2014): 213. http://dx.doi.org/10.1182/blood.v124.21.213.213.

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Abstract Introduction: We recently described the erythroid hormone erythroferrone (ERFE) as a critical regulator of hepcidin production during increased erythropoietic activity. Both anemia of inflammation (AI) and beta-thalassemia are associated with elevated levels of erythropoietin, the signal directing ERFE expression, suggesting that ERFE may play a role in the pathogenesis of these disorders. Indeed, Erfe mRNA expression was highly increased in the bone marrow and the spleen of a mouse model of β-thalassemia Hbbth3/+ (Th3/+). We therefore investigated the role of erythroferrone in hepcidin regulation in anemia of inflammation and β-thalassemia. We report that ERFE contributes to the recovery from anemia of inflammation and may be a hepcidin-suppressive factor responsible for iron accumulation in thalassemia. Methods: We explored the role of ERFE in anemia of inflammation using the heat-killed Brucellaabortus (BA) mouse model of AI. Hepcidin regulation and recovery from anemia was compared between wild-type and Erfe-deficient mice. To determine whether ERFE is the hepcidin-suppressive factor in thalassemia, we generated Erfe-/-/Th3/+ double mutant mice and compared them to their littermate WT, Erfe-/- and Th3/+ mice. Mice were compared at 3, 6 and 12 weeks of age. Results: Compared to wild-type mice, Erfe-deficient mice did not appropriately decrease hepcidin production during recovery from AI and exhibited greater severity of anemia (figure). These data suggest that compensatory hepcidin suppression during the recovery phase of AI is mediated by ERFE. However, in mice this defect was partly compensated by prolonged stimulation of erythropoiesis and higher reticulocytosis resulting in Erfe-deficient mice reaching wild-type hemoglobin levels by day 28 (figure). Figure 1 Figure 1. At the other end of the spectrum, we showed that thalassemic mice exhibited greatly increased expression of Erfe mRNA in the bone marrow and the spleen. Ablation of Erfe in Th3/+ mice restored normal hepcidin levels and significantly reduced serum iron concentration and hepatic iron overload at 6 weeks of age. Comparison of Erfe-/- / Th3/+ and Th3/+ mice at 3, 6 and 12 weeks of age did not show any difference in the severity of the anemia in absence of ERFE suggesting that ERFE regulates hepcidin expression but its absence did not cause iron restriction and did not ameliorate ineffective erythropoiesis. Conclusion: ERFE is a critical regulator of hepcidin expression during recovery from AI and ERFE agonists may alleviate iron restriction in AI. ERFE may also be the factor responsible for hepcidin suppression and secondary iron overload in β-thalassemia. Disclosures Ganz: Intrinsic LifeSciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Keryx Pharma: Consultancy; Merganser Biotech: Consultancy, Equity Ownership.

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Kautz, Leon, Sharraya Aschemeyer, Victoria Gabayan, Tomas Ganz, and Elizabeta Nemeth. "Erythroferrone Regulates Hepcidin Expression Independently of Matriptase 2." Blood 128, no. 22 (December 2, 2016): 3616. http://dx.doi.org/10.1182/blood.v128.22.3616.3616.

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Abstract Introduction: The iron-regulatory hormone hepcidin regulates the body iron stores and its expression is repressed when erythropoietic activity intensifies to meet the iron requirements for erythropoiesis (e.g. during anemia). Under the influence of erythropoietin (EPO), the hormone erythroferrone (ERFE) is secreted by erythroid precursors in the bone marrow and the spleen, and suppresses hepcidin synthesis to facilitate the recovery from anemia. However, the mechanism by which ERFE suppresses hepcidin is unknown. In contrast with forms of anemia in which hepcidin is suppressed, patients with mutations in transmembrane serine protease 6 (TMPRSS6) have iron-refractory iron deficiency anemia (IRIDA) but increased hepcidin production despite a severe anemia and elevated EPO levels. Recently, it has been suggested that matriptase-2 activity facilitates ERFE-mediated suppression of hepcidin. We therefore investigated the potential crosstalk between ERFE and Matriptase 2. Methods: We first measured serum ERFE concentration in Tmprss6-/- mice. To assess the contribution of ERFE to the phenotype of Tmprss6-/-mice, we next generated Tmprss6-/-mice with disrupted Erfe (Erfe+/- Tmprss6-/-; Erfe-/- Tmprss6-/- and Erfe+/+ Tmprss6-/-). To determine whether ERFE requires TMPRSS6 to regulate hepcidin production, we treated freshly isolated hepatocytes from wild-type (WT) or Tmprss6-/- mice with conditioned medium from cells expressing recombinant ERFE or not. Results: While wild-type mice have undetectable plasma ERFE (below the 500 pg/ml limit of detection), plasma ERFE concentration was elevated in Tmprss6-/- to levels comparable to those of WT animals 24 hours after phlebotomy (~3 ng/ml) but was lower than ERFE levels in thalassemic mice (~10 ng/ml). Ablation of Erfe in Tmprss6-/- mice did not result in any change in hematological parameters, hepcidin expression and iron levels compared to Tmprss6-/- animals at 6 weeks of age. However, treatment of WT and Tmprss6-/-hepatocytes with ERFE resulted in a comparable suppression of hepcidin mRNA expression. Conclusion: Although matriptase-2 may dampen the BMP signaling under the influence of EPO, it is not part of the ERFE signaling pathway. Disclosures Ganz: Intrinsic Lifesciences: Other: shareholder and scientific advisor; Merganser Biotech: Other: shareholder and scientific advisor; Silarus therapeutics: Other: shareholder and scientific advisor; Keryx Biopharmaceuticals: Consultancy. Nemeth:Intrinsic Lifesciences: Other: shareholder and scientific advisor; Merganser Biotech: Other: shareholder and scientific advisor; Silarus therapeutics: Other: shareholder and scientific advisor.

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3

Arezes, João, Niall Foy, Kirsty McHugh, Doris Quinkert, Susan Benard, Anagha Sawant, Joe N. Frost, et al. "Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia." Blood 135, no. 8 (February 20, 2020): 547–57. http://dx.doi.org/10.1182/blood.2019003140.

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Abstract Erythroferrone (ERFE) is produced by erythroblasts in response to erythropoietin (EPO) and acts in the liver to prevent hepcidin stimulation by BMP6. Hepcidin suppression allows for the mobilization of iron to the bone marrow for the production of red blood cells. Aberrantly high circulating ERFE in conditions of stress erythropoiesis, such as in patients with β-thalassemia, promotes the tissue iron accumulation that substantially contributes to morbidity in these patients. Here we developed antibodies against ERFE to prevent hepcidin suppression and to correct the iron loading phenotype in a mouse model of β-thalassemia [Hbb(th3/+) mice] and used these antibodies as tools to further characterize ERFE’s mechanism of action. We show that ERFE binds to BMP6 with nanomolar affinity and binds BMP2 and BMP4 with somewhat weaker affinities. We found that BMP6 binds the N-terminal domain of ERFE, and a polypeptide derived from the N terminus of ERFE was sufficient to cause hepcidin suppression in Huh7 hepatoma cells and in wild-type mice. Anti-ERFE antibodies targeting the N-terminal domain prevented hepcidin suppression in ERFE-treated Huh7 cells and in EPO-treated mice. Finally, we observed a decrease in splenomegaly and serum and liver iron in anti–ERFE-treated Hbb(th3/+) mice, accompanied by an increase in red blood cells and hemoglobin and a decrease in reticulocyte counts. In summary, we show that ERFE binds BMP6 directly and with high affinity, and that antibodies targeting the N-terminal domain of ERFE that prevent ERFE–BMP6 interactions constitute a potential therapeutic tool for iron loading anemias.

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Han, Huiling, Keith Westerman, Vaughn Ostland, Patrick Gutschow, Gordana Olbina, Jacqueline da Silva Guimarães, Juçara Gastaldi Cominal, et al. "A Novel Dual Monoclonal Sandwich ELISA for Human Erythroferrone." Blood 128, no. 22 (December 2, 2016): 1272. http://dx.doi.org/10.1182/blood.v128.22.1272.1272.

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Abstract Erythroferrone (ERFE) is a hormone produced by erythroblasts in the bone marrow in response to erythropoietin (EPO). Recent animal studies have shown that rather than being involved in regulation of baseline erythropoiesis, ERFE acts as a stress erythropoiesis-specific regulator of hepcidin expression. By suppressing hepcidin expression in the liver, EFRE contributes to increased dietary iron absorption and recycling of stored iron necessary for recovery of blood mass after hemorrhage. In addition, ERFE was found to be involved in hepcidin regulation in inherited iron loading anemias, such as b-Thalassemia. ERFE has potential as a clinical marker for assessing erythropoiesis in patients with blood disorders. To date, there have been no reports of a human ERFE assay development and validation. To study the biological function and potential clinical applications of ERFE in humans, we developed the first dual monoclonal sandwich ELISA for serum measurement. Purified recombinant ERFE was used as antigen to immunize mice and subsequently screen 3000 hybridomas for binding to human ERFE. The nine positive hybridomas were expanded and monoclonal antibody from each clone purified and isotyped. We biotinylated each antibody and queried all possible combinations of capture and detection antibodies for binding activity. We discovered at least two pairs of antibodies suitable for assay optimization. Two mAbs were selected, 4C1 and 2D2, as the capture and detection antibody, respectively. We used streptavidin-HRP to quantify binding and detection of ERFE. The ERFE ELISA standard curve ranges from 0-50 ng/mL. The assay's lower limit of detection (LLOD) is 0.15 ng/mL and lower limit of quantitation (LLOQ) is 0.17 ng/mL. We assessed the normal range of ERFE by analyzing serum from110 healthy first time blood donors with normal iron status determined by assessment of ferritin, plasma iron, and transferrin saturation. Serum ERFE in the first time blood donors ranged from 0.15 to 3.94 ng/mL with a mean of 0.83 ng/mL. To re-capitulate the animal data previously observed in mice (Kautz et al., Nat Genet. 2014; 46(7): 678-684), we examined the effect of blood donation on human serum ERFE concentrations (Figure 1). We analyzed sera from three donors which underwent platelet and plasma-apheresis at baseline and day 2, 3, 4, 5, 7, 9, 10, 14, and 120 (Li et al., J Clin Apher., 2016). It was estimated that 30ml of RBCs were lost in the procedure. Serum ERFE concentrations were elevated from baseline in each patient within 2 days and remained higher through 14 days. At 120 days serum ERFE returned to baseline levels. We went on to test the concept that serum ERFE concentrations would be elevated in blood disorders associated with ineffective erythropoiesis, we obtained serum samples from X-linked sideroblastic anemia probands and 15 of their family members. Nine of the probands had point mutation in the ALAS2 gene and two had a-globin duplications. We measured serum ERFE in the probands and family controls and discovered that ERFE was significantly increased in probands relative to familial controls (Figure 2). Family members had ERFE concentrations similar to healthy first time blood donors (<1 ng/ml). An additional study was conducted to examine ERFE in thalassemia patients whom are known to exhibit ineffective erythropoiesis due to mutations in the α- or β-globin genes that cause production of deformed red blood cells. We obtained sera from patients with both α- and β-thalassemia and discovered that both β+-thalassemia and β0-thalassemia patients had significantly higher serum ERFE concentrations than controls and a group of iron deficient (ID) controls (Figure 3). The β0-thalassemia patients had highly elevated serum ERFE which is likely due to the degree that erythropoiesis is affected. The data we present lends strong support to the quality of the dual monoclonal sandwich ELISA we have developed. The ERFE assay is very sensitive, has excellent reproducibility and spike recovery characteristics, and is easy to perform. The physiological and clinical data we present supports the assertion that the assay is specific for ERFE and will allow insight into a number of hematological diseases. Figure 1 Effect of plasma- or platelet-apheresis on ERFE. Figure 1. Effect of plasma- or platelet-apheresis on ERFE. Figure 2 ERFE in X-linked Sideroblastic Anemia. ****p<0.0001 Figure 2. ERFE in X-linked Sideroblastic Anemia. ****p<0.0001 Figure 3 ERFE in Iron Deficient and Thalassemic Patients. ****p<0.0001, **p<0.005 Figure 3. ERFE in Iron Deficient and Thalassemic Patients. ****p<0.0001, **p<0.005 Disclosures Han: Intrinsic Lifesciences.: Employment, Equity Ownership. Westerman:Intrinsic LifeSciences: Employment. Ostland:Intrinsic LifeScienc s: Employment, Equity Ownership. Gutschow:Intrinsic LifeSciences: Employment, Equity Ownership. Olbina:Intrinsic LifeSciences: Employment, Equity Ownership. Westerman:Intrinsic LifeSciences: Employment, Equity Ownership.

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Gutschow, Patrick, Huiling Han, Gordana Olbina, Keith Westerman, Eileen Westerman, Marc Ruiz Martinez, Yelena Ginzburg, Elizabeta Nemeth, Tomas Ganz, and Vaughn Ostland. "A Novel Sandwich ELISA to Quantify Erythroferrone in Mouse Serum." Blood 134, Supplement_1 (November 13, 2019): 2237. http://dx.doi.org/10.1182/blood-2019-130947.

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Erythroferrone (ERFE) is a hormone produced by erythroblasts in response to erythropoietin. ERFE acts as a regulator of hepcidin expression during stress erythropoiesis. By suppressing hepcidin expression, ERFE contributes to the mobilization of dietary and stored iron necessary for recovery from blood loss after hemorrhage. Furthermore, overproduction of ERFE plays a pathogenic role in β-thalassemia and other anemias with ineffective erythropoiesis, where it contributes to hepcidin suppression and consequent iron overload. Development of a method to quantify serum ERFE in mice would improve our ability to study the pathobiology of this erythroid regulator. A dual polyclonal sandwich ELISA was developed to quantify ERFE in mouse serum. Purified recombinant mouse ERFE was used to immunize rabbits and goats, and high titer antibodies were purified from serum via protein A. Western blotting of reduced ERFE protein demonstrated that both the capture and detection antibody specifically recognized mouse ERFE, weakly recognized recombinant human ERFE, but neither antibody recognized mouse, rabbit or human TNF-alpha. Antibody was biotinylated and screened to determine the optimal antibody pairs. ELISA optimization established the standard curve range from 0 to 4 ng/ml. With a 10% sample dilution the lower limit of quantitation (LLOQ) was 0.1 ng/ml. Average spike recovery of ERFE in 3 different mouse sera (0.75 - 24 ng/ml) ranged from 93-105% (mean 99%). Dilutional linearity of the same spiked samples ranged from 93-104% (mean 99%). Intra- and inter-assay precision was 4.9% and 3.9%, respectively, over a concentration range of 0.57 - 16.3ng/ml. The effect of phlebotomy on serum ERFE in 6- and 8-week-old male C57BL/6 mice (n=3 each) was examined 24 h after removal of 0.5 ml of blood (Figure 1). At time 0, all the mice had serum ERFE levels below the limit of detection, but serum ERFE had increased to a mean of 1.9 ng/ml at 24 hours (P=0.03). This increase in ERFE is associated with a decrease in hepcidin from 209 ng/ml to 104 ng/ml (p<0.0001). In a mouse model of β-Thalassemia (th3/+) there was significantly greater ERFE (1.2 ng/ml, n=5) compared to wild type (wt, <0.1 ng/ml, n=3, p < 0.04). Crossing the th3/+ mice with transferrin receptor 1 (TfR1) heterozygous mice (th3/+ TfR1+/-) produced a partial rescue of ERFE (0.6 ng/ml, n=5). Erfe knockout mice (th3/+ erfe-/- and th3/+ TfR1+/- erfe-/-) produced significantly less ERFE (p<0.02) than their respective single and double mutants (<0.1 ng/ml [n=7] and <0.1 ng/ml [n=4], respectively) (Figure 2). Collectively, this validated ELISA can quantify mouse serum ERFE in both healthy and diseased mouse models and can be used to study the pathobiology of this erythroid regulator in diseases associated with ineffective erythropoiesis. Disclosures Gutschow: Intrinsic LifeSciences: Employment, Equity Ownership. Han:Intrinsic LifeSciences: Employment, Equity Ownership. Olbina:Intrinsic LifeSciences: Employment, Equity Ownership. Westerman:Intrinsic LifeSciences: Employment, Equity Ownership. Westerman:Intrinsic LifeSciences: Employment, Equity Ownership. Ginzburg:La Jolla Pharma: Membership on an entity's Board of Directors or advisory committees. Nemeth:Silarus Therapeutics: Consultancy, Equity Ownership; Ionis Pharmaceuticals: Consultancy; Protagonist: Consultancy; La Jolla Pharma: Consultancy; Intrinsic LifeSciences: Consultancy, Equity Ownership; Keryx: Consultancy. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership. Ostland:Intrinsic LifeSciences: Employment, Equity Ownership.

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Delaney, Katherine, Ronnie Guillet, Eva Pressman, Elizabeta Nemeth, and Kimberly O'Brien. "Erythroferrone Is Associated with Maternal Erythropoietic Drive During Pregnancy." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 968. http://dx.doi.org/10.1093/cdn/nzaa054_040.

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Abstract Objectives Iron (Fe) homeostasis must be tightly regulated during pregnancy to meet both maternal and fetal Fe demands. Several hormones are known to impact Fe homeostasis including hepcidin, erythropoietin and erythroferrone (ERFE). Few data are available on determinants of ERFE in pregnant women or in their newborns at birth. The objective of this study was to characterize concentrations of ERFE across gestation and evaluate this hormone in relation to other Fe status biomarkers and regulatory hormones in mothers across pregnancy. Methods ERFE was measured in serum from pregnant adolescents (n = 166, age 14–19) or women carrying multiple fetuses (n = 61, age 20–46). ERFE concentrations across gestation (wks 8 – 42.1) were compared to Fe status and nutritional indicators (hemoglobin (Hb), serum ferritin (SF), soluble transferrin receptor (sTfR), total body Fe (TBI), TR-F index (sTfR/log(SF)), folate and vitamin B-12), as well as regulatory hormones (erythropoietin (EPO), hepcidin) and inflammatory markers (IL-6, C-reactive protein (CRP)). Results ERFE concentrations increased significantly across pregnancy in women carrying multiple fetuses (P < 0.01), but did not change across pregnancy in the adolescents (P = 0.3). In both populations, 16% (n = 30) of women were anemic at midgestation (MG) and 24% (n = 75) at delivery. ERFE concentrations were significantly increased in anemic women at both MG (P = 0.02) and at delivery (P = 0.02). At MG (median 26 wks), ERFE was significantly positively associated with TfR (P < 0.001) and EPO (P = 0.002). Maternal TfR, IL-6 and serum Fe were the strongest determinants of maternal MG ERFE, and explained 29% of variance in ERFE. At delivery (median 38 wks), ERFE was significantly positively associated with TfR (P < 0.001) and EPO (P < 0.001), which together explained 18% of variance in ERFE at delivery. ERFE was not significantly associated with hepcidin at either MG (P = 0.87) or delivery (P = 0.52). Conclusions ERFE was significantly higher in anemic women across pregnancy and, as expected, was positively associated with indicators of erythropoietic drive. ERFE however, was not significantly associated with hepcidin, possibly because hepcidin is regulated by multiple competing signals. More research is needed to understand the relationship between maternal ERFE and neonatal Fe status at birth. Funding Sources Funded by the NIH (NIDDK/NICHD).

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Arezes, Joao, Niall Foy, Kirsty McHugh, Anagha Sawant, Susan Benard, Doris Quinkert, Virginie Terraube, et al. "Erythroferrone Inhibits the Induction of Hepcidin By BMP6." Blood 132, Supplement 1 (November 29, 2018): 850. http://dx.doi.org/10.1182/blood-2018-99-111140.

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Abstract Decreased hepcidin mobilizes iron, which facilitates erythropoiesis, but excess iron is pathogenic in beta-thalassemia and other iron-loading anaemias. Erythropoietin (EPO) enhances erythroferrone (ERFE) synthesis by erythroblasts, and ERFE suppresses hepatic hepcidin production, through an unknown mechanism. The BMP/SMAD pathway in the liver is critical for control of hepcidin, and we show that EPO suppressed hepcidin and other BMP target genes in vivo in a partially ERFE-dependent manner. Furthermore, recombinant ERFE suppressed the hepatic BMP/SMAD pathway independently of changes in serum and liver iron, and in vitro, ERFE decreased SMAD 1/5/8 phosphorylation and inhibited expression of BMP target genes in hepatoma cells. ERFE specifically abrogated the induction of hepcidin by BMP5, BMP6 and BMP7, but had no or very little effect on hepcidin induction by BMP2, 4, 9 or Activin B. A neutralising anti-ERFE antibody prevented the ability of ERFE to inhibit hepcidin induction by BMP5, 6 and 7. Cell-free Homogeneous Time Resolved Fluorescence assays showed that BMP5, BMP6 and BMP7 competed with anti-ERFE for binding to ERFE. Biacore analysis showed that ERFE binds to BMP6 with a higher affinity compared to its binding to BMP2, BMP4 or Activin B, and does not bind to GDF15. We propose that ERFE suppresses hepcidin by inhibiting hepatic BMP/SMAD signaling via preferentially binding and impairing the function of an evolutionarily closely related BMP sub-group consisting of BMP5, BMP6 and BMP7. These findings indicate that ERFE can act as a natural ligand trap generated by stimulated erythropoiesis in order to regulate availability of iron. Disclosures Arezes: Pfizer: Research Funding. Foy:Pfizer: Employment. McHugh:Pfizer: Research Funding. Sawant:Pfizer: Employment. Benard:Pfizer: Employment. Quinkert:Pfizer: Research Funding. Terraube:Pfizer: Employment. Brinth:Pfizer: Employment. Tam:Pfizer: Employment. LaVallie:Pfizer: Employment. Cunningham:Pfizer: Employment. Lambert:Pfizer: Employment. Draper:Pfizer: Research Funding. Jasuja:Pfizer: Employment. Drakesmith:La Jolla Pharmaceutical Company: Research Funding; Pfizer: Research Funding; Alnylam: Consultancy; Kymab: Membership on an entity's Board of Directors or advisory committees.

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Than, Min Min, Pimpisid Koonyosying, Jetsada Ruangsuriya, Sunhawit Junrungsee, Chairat Uthaipibull, and Somdet Srichairatanakool. "Effect of Recombinant Human Erythroferrone Protein on Hepcidin Gene (Hamp1) Expression in HepG2 and HuH7 Cells." Materials 14, no. 21 (October 28, 2021): 6480. http://dx.doi.org/10.3390/ma14216480.

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Iron is essential for all living organisms. It is strictly controlled by iron transporters, transferrin receptors, ferroportin and hepcidin. Erythroferrone (ERFE) is an iron-regulatory hormone which is highly expressed in erythroblasts by erythropoietin (EPO) stimulation and osteoblasts independently of EPO by sequestering bone morphogenetic proteins and inhibiting hepatic hepcidin expression. Although the hepcidin suppressive function of ERFE is known, its receptors still require investigation. Here, we aim to identify ERFE receptors on the HepG2 and Huh7 cells responsible for ERFE. Recombinant ERFE (rERFE) was first produced in HEK293 cells transfected with pcDNA3.1 + ERFE, then purified and detected by Western blot. The liver cells were treated with an rERFE-rich medium of transfected HEK293 cells and a purified rERFE-supplemented medium at various time points, and hepcidin gene (Hamp1) expression was determined using qRT-PCR. The results show that 37-kD rERFE was expressed in HEK293 cells. Hamp1 was suppressed at 3 h and 6 h in Huh7 cells after rERFE treatments (p < 0.05), then restored to the original levels. Hamp1 was activated after treatment with purified rERFE for 24 h and 48 h. Together, these results reveal that ERFE suppressed Hamp1 expression in liver cells, possibly acting on membrane ERFE receptor, which in Huh7 cells was more sensitive to the ERFE concentrate.

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Xu, Qingyu, Eva Altrock, Nanni Schmitt, Alexander Streuer, Felicitas Rapp, Verena Nowak, Julia Obländer, et al. "In Silico Pan-Cancer Analysis Reveals Prognostic Role of the Erythroferrone (ERFE) Gene in Human Malignancies." International Journal of Molecular Sciences 24, no. 2 (January 15, 2023): 1725. http://dx.doi.org/10.3390/ijms24021725.

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The erythroferrone gene (ERFE), also termed CTRP15, belongs to the C1q tumor necrosis factor-related protein (CTRP) family. Despite multiple reports about the involvement of CTRPs in cancer, the role of ERFE in cancer progression is largely unknown. We previously found that ERFE was upregulated in erythroid progenitors in myelodysplastic syndromes and strongly predicted overall survival. To understand the potential molecular interactions and identify cues for further functional investigation and the prognostic impact of ERFE in other malignancies, we performed a pan-cancer in silico analysis utilizing the Cancer Genome Atlas datasets. Our analysis shows that the ERFE mRNA is significantly overexpressed in 22 tumors and affects the prognosis in 11 cancer types. In certain tumors such as breast cancer and adrenocortical carcinoma, ERFE overexpression has been associated with the presence of oncogenic mutations and a higher tumor mutational burden. The expression of ERFE is co-regulated with the factors and pathways involved in cancer progression and metastasis, including activated pathways of the cell cycle, extracellular matrix/tumor microenvironment, G protein-coupled receptor, NOTCH, WNT, and PI3 kinase-AKT. Moreover, ERFE expression influences intratumoral immune cell infiltration. Conclusively, ERFE is aberrantly expressed in pan-cancer and can potentially function as a prognostic biomarker based on its putative functions during tumorigenesis and tumor development.

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Miura, Shogo, Masayoshi Kobune, Soushi Ibata, Masahiro Yoshida, Satoshi Iyama, Tsutomu Sato, Kazuyuki Murase, et al. "CD34/EPO-R Double Positive MDS Cells Produce Erythroferrone in Response to Erythropoietin." Blood 128, no. 22 (December 2, 2016): 2455. http://dx.doi.org/10.1182/blood.v128.22.2455.2455.

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Abstract Background. It has been reported that iron absorption from gastrointestinal tract was enhanced in a subset of patients with myelodysplastic syndrome (MDS) exhibiting ineffective erythropoiesis. Iron absorption was achieved via an iron transporter ferroportin which was downregulated by hepcidin. Recently, three erythroid regulators such as growth differentiation factor 15 (GDF15), twisted gastrulation protein homolog 1 (TWSG1) and erythroferrone (ERFE) which down regulated hepatic hepcidin production has been identified. However, it has been not yet clarified which molecules could contribute to the increased iron absorption in patients with MDS. Materials and Methods. In the present study, we examined the expression level of GDF15, TWSG1 and ERFE mRNA during ex vivo erythroid differentiation from CD34+ bone marrow (BM) cells in the presence of 4 U/mL erythropoietin (EPO), 100 U/mL interleukin-3, 10 ng/mL stem cell factor, 20 ng/mL insulin-like growth factor (IGF)-1 and 500 micro g/mL iron-saturated transferrin. We further analyzed the expression level of GDF15 and ERFE in BM mononuclear cells (MNCs) derived from BM derived from MDS patients and lymphoma patients without BM involvement as a control by using quantitive RT-PCR. The expression of EPO-R was analyzed by flow cytometry. The CD34+ MDS cells were seeded on fibronectin substratum in 5 mL of a serum-free medium supplemented with 50 ng/mL human thrombopoietin (TPO), 10 ng/mL human SCF, 50 ng/mL human Fms-related tyrosin kinase 3 ligand (FLT3LG) and 100 ng/mL human delta like protein 4 (DLL4) with or without 4 U/mL EPO. For analysis of CD34+ cells, a GEO dataset (GSE58831) was downloaded as a matrix by GEOquery package (Bioconductor). The numerical data of the matrix were normalized by quantile normalization using limma package. Clinical and sequencing data were downloaded from supplementary materials. Those were combined with a GEO dataset (GSE58831) before analysis. Results. The level of ERFE mRNA was dramatically increased during erythroid differentiation from control CD34+ cells in response to EPO in vitro (Figure 1) although increase of the level of GDF15 and TWSG1 was marginal. Moreover, the level of ERFE mRNA in BM MNCs derived from MDS patients was significantly higher than that from control. Furthermore, the expression level of ERFE mRNA correlated with the percentage of CD34+ cells, but not percentage of erythroblasts derived from MDS patients. Using GEO data sets (GSE58831), the level of ERFE mRNA in CD34+ cells derived from MDS patients was significantly elevated as compared with that from healthy volunteers. Importantly, flow cytometric analysis indicated that CD34+ MDS cells highly expressed EPO receptors and the level of ERFE mRNA in CD34+ cells in a subset of MDS patients was enhanced after exposure of EPO ex vivo. In addition, the level of ERFE mRNA positively correlated with the level of EPO-R in CD34+ MDS cells (GSE58831). Conclusion. These results indicated that CD34+/EPO-R+ double positive MDS cells is one of the major sources of ERFN. The level of ERFE in CD34+ MDS cells may be associated with abnormal iron metabolism in MDS patients. These finding may be important for understanding the abnormal iron metabolism and predicting the efficacy of EPO administration. Disclosures No relevant conflicts of interest to declare.

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Coffey, Richard, Grace Jung, Joseph D. Olivera, Gabriel Karin, Renata C. Pereira, Elizabeta Nemeth, and Tomas Ganz. "Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice." Blood 139, no. 3 (January 20, 2022): 439–51. http://dx.doi.org/10.1182/blood.2021014054.

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Abstract The hormone erythroferrone (ERFE) is produced by erythroid cells in response to hemorrhage, hypoxia, or other erythropoietic stimuli, and it suppresses the hepatic production of the iron-regulatory hormone hepcidin, thereby mobilizing iron for erythropoiesis. Suppression of hepcidin by ERFE is believed to be mediated by interference with paracrine bone morphogenetic protein (BMP) signaling that regulates hepcidin transcription in hepatocytes. In anemias with ineffective erythropoiesis, ERFE is pathologically overproduced, but its contribution to the clinical manifestations of these anemias is not well understood. We generated 3 lines of transgenic mice with graded erythroid overexpression of ERFE and found that they developed dose-dependent iron overload, impaired hepatic BMP signaling, and relative hepcidin deficiency. These findings add to the evidence that ERFE is a mediator of iron overload in conditions in which ERFE is overproduced, including anemias with ineffective erythropoiesis. At the highest levels of ERFE overexpression, the mice manifested decreased perinatal survival, impaired growth, small hypofunctional kidneys, decreased gonadal fat depots, and neurobehavioral abnormalities, all consistent with impaired organ-specific BMP signaling during development. Neutralizing excessive ERFE in congenital anemias with ineffective erythropoiesis may not only prevent iron overload but may have additional benefits for growth and development.

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Kautz, Léon, Grace Jung, Xin Du, Victoria Gabayan, Justin Chapman, Marc Nasoff, Elizabeta Nemeth та Tomas Ganz. "Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia". Blood 126, № 17 (22 жовтня 2015): 2031–37. http://dx.doi.org/10.1182/blood-2015-07-658419.

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Abstract Inherited anemias with ineffective erythropoiesis, such as β-thalassemia, manifest inappropriately low hepcidin production and consequent excessive absorption of dietary iron, leading to iron overload. Erythroferrone (ERFE) is an erythroid regulator of hepcidin synthesis and iron homeostasis. Erfe expression was highly increased in the marrow and spleen of HbbTh3/+ mice (Th3/+), a mouse model of thalassemia intermedia. Ablation of Erfe in Th3/+ mice restored normal levels of circulating hepcidin at 6 weeks of age, suggesting ERFE could be a factor suppressing hepcidin production in β-thalassemia. We examined the expression of Erfe and the consequences of its ablation in thalassemic mice from 3 to 12 weeks of age. The loss of ERFE in thalassemic mice led to full restoration of hepcidin mRNA expression at 3 and 6 weeks of age, and significant reduction in liver and spleen iron content at 6 and 12 weeks of age. Ablation of Erfe slightly ameliorated ineffective erythropoiesis, as indicated by reduced spleen index, red cell distribution width, and mean corpuscular volume, but did not improve the anemia. Thus, ERFE mediates hepcidin suppression and contributes to iron overload in a mouse model of β-thalassemia.

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Delaney, Katherine M., Ronnie Guillet, Eva K. Pressman, Tomas Ganz, Elizabeta Nemeth, and Kimberly O. O'Brien. "Umbilical Cord Erythroferrone Is Inversely Associated with Hepcidin, but Does Not Capture the Most Variability in Iron Status of Neonates Born to Teens Carrying Singletons and Women Carrying Multiples." Journal of Nutrition 151, no. 9 (June 3, 2021): 2590–600. http://dx.doi.org/10.1093/jn/nxab156.

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ABSTRACT Background The developing fetus requires adequate iron and produces its own hormones to regulate this process. Erythroferrone (ERFE) is a recently identified iron regulatory hormone, and normative data on ERFE concentrations and relations between iron status and other iron regulatory hormones at birth are needed. Objectives The objective of this study was to characterize cord ERFE concentrations at birth and assess interrelations between ERFE, iron regulatory hormones, and iron status biomarkers in 2 cohorts of newborns at higher risk of neonatal anemia. Methods Umbilical cord ERFE concentrations were measured in extant serum samples collected from neonates born to women carrying multiples (age: 21–43 y; n = 127) or teens (age: 14–19 y; n = 164). Relations between cord blood ERFE and other markers of iron status or erythropoiesis in cord blood were assessed by linear regression and mediation analysis. Results Cord ERFE was detectable in all newborns delivered between 30 and 42 weeks of gestation, and mean concentration at birth was 0.73 ng/mL (95% CI: 0.63, 0.85 ng/mL). Cord ERFE was on average 0.25 ng/mL lower in newborns of black as opposed to white ancestry (P = 0.04). Cord ERFE was significantly associated with transferrin receptor (β: 1.17, P < 0.001), ferritin (β: −0.27, P < 0.01), and hemoglobin (Hb) (β: 0.04, P < 0.05). However, cord hepcidin and the hepcidin:erythropoietin (EPO) ratio captured the most variance in newborn iron and hematologic status (>25% of variance explained). Conclusions Neonates born to teens and women carrying multiples were able to produce ERFE in response to neonatal cord iron status and erythropoietic demand. ERFE, however, did not capture significant variance in newborn iron or Hb concentrations. In these newborns, cord hepcidin and the hepcidin:EPO ratio explained the most variance in iron status indicators at birth.

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Silvestri, Laura, Grazia Rita Gelsomino, Antonella Nai, Marco Rausa, Alessia Pagani, and Clara Camaschella. "Is Tmprss6 Required for Hepcidin Inhibition By Erythroferrone?" Blood 124, no. 21 (December 6, 2014): 1347. http://dx.doi.org/10.1182/blood.v124.21.1347.1347.

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Abstract Introduction Hepcidin, the main regulator of iron homeostasis, is inhibited when erythropoiesis is expanded. Several candidates, as GDF15 and TWSG1, have been proposed to mediate this effect but their role remains unproven. Recently, erythroferrone (ERFE), a member of the C1q/tumors necrosis factor-related protein family, has been identified as a new hepcidin inhibitor (Kautz et al., 2014). ERFE is an erythropoietin (EPO) target gene produced by bone marrow and spleen erythroblasts in conditions of stress erythropoiesis, as after bleeding or EPO treatment, and in ineffective erythropoiesis, as in beta thalassemia. Inhibiting hepatocyte hepcidin, ERFE coordinates erythroid differentiation with iron availability. In beta-thalassemia Hbbth3/+ mice, inactivation of Erfe partially reduces liver iron content, suggesting that increased Erfe production contributes to thalassemia iron overload (Kautz et al., 2014). Here we analyzed spleen Erfe expression in models of low (iron loaded Hjv-/- and Tfr2-/- mice) and high (iron deficient, Tmprss6-/- mice) hepcidin, in secondary iron overload (Hbbth3/+ mice), in Hbbth3/+ Tmprss6-/- and Tfr2-/- Tmprss6-/- double mutants and in mice with a diet-induced iron deficiency. Methods Mice were maintained in accordance with the European Union guidelines. The study was approved by the IACUC of San Raffaele Scientific Institute, Milan, Italy. Hjv-/-, Tfr2-/-, Tmprss6-/- and double mutant (Tfr2-/- Tmprss6-/- or Hbbth3/+ Tmprss6-/-) adult male mice were studied. A group of adult wild type mice was maintained an iron-deficient diet (ID, <3 mg/kg iron) for 3 weeks. Appropriate controls were studied. Gene expression levels were measured by quantitative real-time-PCR. Hematological and iron parameters and serum erythropoietin were studied using standard procedures. Results We confirm that Erfe is increased in the spleen of Hbbth3/+ mice, characterized by anemia, ineffective erythropoiesis, high EPO, low hepcidin and iron overload. Erfe is upregulated also in Tmprss6-/- iron deficient animals, consistent with their increased serum Epo. However, their high hepcidin levels suggest that Tmprss6 is indispensable for Erfe-mediated hepcidin inhibition. Consistent with this interpretation, in Hbbth3/+Tmprss6-/- double mutant mice, in which ineffective erythropoiesis and anemia are partially rescued (Nai et al., 2012), hepcidin levels are higher than in Hbbth3/+ and comparable to those of Tmprss6-/- mice, although Erfe remains high and serum Epo levels are similarly increased in all the three genotypes (Tmprss6-/-, Hbbth3/+, Hbbth3/+Tmprss6-/-). To further confirm the need of Tmprss6 for Erfe function, in diet-induced iron deficient animals, in which Tmprss6 is supposed to be active, Erfe expression is increased and hepcidin strongly downregulated. In the spleen of Hjv-/- and Tfr2-/- mice, the expression of the erythroid markers Tfr1 and Glycophorin A (Gypa) is decreased, suggesting that splenic erythropoiesis is reduced in iron overload. In agreement Erfe is downregulated in Tfr2-/- and mildly decreased in Hjv-/- mice. Genetic inactivation of Tmprss6 in Tfr2-/- mice enhances Erfe, Tfr1 and Gypa expression and serum Epo to levels comparable to Tmprss6-/- mice and increases hepcidin although at levels lower than those found in Tmprss6-/-. Conclusions Erfe upregulation in iron deficiency indicates that it is a general mediator of hepcidin inhibition. In Tmprss6-/- mice, notwithstanding Erfe upregulation, hepcidin levels are not suppressed, suggesting that Erfe acts upstream Tmprss6, although results in the double mutant Tfr2-/-Tmprss6-/- require further studies. In disease models of iron overload Erfe expression is downregulated, consistent with decreased splenic erythropoiesis. The mechanisms of hepcidin inhibition by Erfe still remain to be investigated. Disclosures No relevant conflicts of interest to declare.

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Tomczyk, Maja, Jakub Kortas, Damian Flis, Barbara Kaczorowska-Hac, Agata Grzybkowska, Andzelika Borkowska, Ewa Lewicka, Alicja Dabrowska-Kugacka, and Jędrzej Antosiewicz. "Marathon Run-induced Changes in the Erythropoietin-Erythroferrone-Hepcidin Axis are Iron Dependent." International Journal of Environmental Research and Public Health 17, no. 8 (April 17, 2020): 2781. http://dx.doi.org/10.3390/ijerph17082781.

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Alterations in iron metabolism after physical activity are manifested through the rise of blood hepcidin (Hpc) levels. However, in many athletes, no changes in Hpc levels are observed after exercise despite the presence of inflammation. The missing links could be erythropoietin (EPO) and erythroferrone (ERFE), which down-regulate Hpc biosynthesis. EPO, ERFE and Hpc biosynthesis is modified by serum iron through transferrin receptor 2. Consequently, we investigated whether marathon-induced changes in EPO, ERFE and Hpc levels are blood iron-dependent. Twenty-nine healthy male marathon runners were analyzed. Serum iron, ferritin, transferrin, EPO, ERFE and Hpc levels were assessed before, immediately after, and 9 ± 2 days after the marathon. The runners whose serum Hpc decreased after the marathon (n = 15), showed a significant increase in ERFE levels. In athletes whose serum iron levels were below 105 µg/day (n = 15), serum EPO (p = 0.00) and ERFE levels (p = 0.00) increased with no changes in Hpc concentration. However, in athletes with low serum iron, no changes in EPO levels were observed when serum ferritin exceeded 70 ng/mL (n = 7). Conversely, an increase in ERFE levels was observed in marathoners with low serum iron, independently of serum ferritin (n = 7). This indicates modulation of blood iron may affect exercise-induced changes in the EPO/ERFE/Hpc axis. Further study is needed to fully understand the physiological meaning of the interdependence between iron and the EPO/ERFE/Hpc axis.

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Castro-Mollo, Melanie, Marc Ruiz Martinez, Maria Feola, Anisa Azatovna Gumerova, Carla Casu, Robert E. Fleming, Stefano Rivella, Tony Yuen, Mone Zaidi та Yelena Ginzburg. "Erythroferrone Regulates Bone Remodeling in β-Thalassemia". Blood 134, Supplement_1 (13 листопада 2019): 2. http://dx.doi.org/10.1182/blood-2019-125822.

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Erythropoiesis normally occurs in the bone marrow within the pelvis and femur, and both erythropoiesis and bone metabolism are susceptible to changes in iron homeostasis. Thus, hematopoietic and osteoid systems require coordination of iron metabolism during stress or ineffective erythropoiesis. Recently, a more extensive understanding of the crosstalk between iron metabolism and erythropoiesis revealed that a bone marrow secreted protein, erythroferrone (ERFE), is a negative regulator of hepcidin [Kautz Nat Gen 2014]. Hepcidin in turn is the main negative regulator of iron absorption and recycling [Nemeth Science 2004] and its suppression enables an increase in iron availability during stress erythropoiesis. Diseases of ineffective erythropoiesis, such as β-thalassemia, with chronic erythroid expansion, are associated with thinning of cortical bone, leading to decreased bone mineral density [Haidar Bone 2011; Vogiatzi Bone 2006]. Mechanisms underlying coordination of erythropoiesis and bone metabolism are incompletely understood. However, because ERFE functions to suppress hepcidin by sequestering BMPs [Arezes Blood 2018], and because BMPs are crucially important for bone metabolism [Hogan Genes Dev 1996], we hypothesize that ERFE may be involved in coordinating iron metabolism, erythropoiesis, and bone homeostasis. Lastly, osteoblast expression of TfR2 was found to inhibit bone formation by activating BMP-p38MAPK signaling and expression of the Wnt inhibitor Sclerostin, protein product of the SOST gene [Rauner Nat Med 2019]. We thus propose to explore the role of ERFE in disordered bone metabolism in β-thalassemia. In vitro data demonstrates that osteoblasts from wild type (WT) mice express ERFE and this expression is enhanced by BMP2/6/7 (Figure 1a and 1b). Furthermore, osteoblasts from ERFE-/- mice exhibit enhanced bone mineralization (6.8-fold increased von Kossa staining, measured by image J) (Figure 1c), increased expression of osteoblast-specific markers (e.g. osterix (OSX))(Figure 1d), and higher SOST expression (Figure 1e) relative to WT osteoblasts. We anticipate that if TfR2 is central to bone metabolism, ERFE-/- osteoblasts may exhibit a decrease in TfR2; our results demonstrate only a trend toward decreased TfR2 in ERFE-/- osteoblasts (Figure 1f). In addition, we propose that ERFE is a negative regulator of osteoblast activity, predicting that ERFE loss in th3/+ mice would enhance bone mineral density. To this end, we analyzed bone mineral density and histomorphometry in WT, ERFE-/-, th3/+, and th3/+ERFE-/- mice. Surprisingly, although no differences are evident between WT, ERFE-/-, and th3/+ femora, th3/+ERFE-/- mice exhibit a decrease in bone mineral density and bone volume / total volume (BV/TV) (Figure 2a-2b) with a trend toward enhanced femoral mineral apposition rate (Figure 2c) relative to th3/+ mice. These results indicate enhanced osteoblast activity without increased bone formation. Because bone mineralization is a composite of the relative osteoblast and osteoclast activity, we hypothesize that osteoclast activity is further enhanced in th3/+ ERFE-/- mice. TRAP staining demonstrates a significantly increased number of osteoclasts in ERFE-/- relative to WT as well as th3/+ ERFE-/- relative to th3/+ femora (Figure 2d). Our studies demonstrate that ERFE, like other members of the TNFα superfamily [Lu J Bone Miner Res 2011], negatively regulates OSX which is critical for osteoblast function (Figure 3a). Thus, suppression of ERFE results in more OSX (Figure 1d), enhanced mineralization (Figure 1c), and higher SOST expression (Figure 1e) which results in the secretion of Sclerostin (Figure 3b). Sclerostin both feeds back to suppress Wnt signaling to decrease osteoblast function and increases RANKL production to stimulate osteoclast differentiation (Figure 3b). Taken together, ERFE functions as a negative regulator of both osteoblast and especially osteoclast activity such that its loss leads to more osteoclast activity and results in decreased bone mineral density in β-thalassemia. These findings provide novel insights into the complex interplay between regulation of iron metabolism and bone homeostasis in diseases of dysregulated erythropoiesis, when ERFE expression is increased, and support the rationale to further explore the role of ERFE and TfR2 in this crosstalk in β-thalassemia. Disclosures Fleming: Protagonist: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Consultancy; Ultragenyx: Consultancy. Rivella:Disc medicine, Protagonist, LIPC, Meira GTx: Consultancy; Meira GTx, Ionis Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Ginzburg:La Jolla Pharma: Membership on an entity's Board of Directors or advisory committees.

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Nemeth, Elizabeta, Tomas Ganz, and Léon Kautz. "Erythron to the Liver: Send Iron." Blood 124, no. 21 (December 6, 2014): SCI—37—SCI—37. http://dx.doi.org/10.1182/blood.v124.21.sci-37.sci-37.

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For successful expansion of erythropoiesis, the activity of the hormone erythropoietin (EPO) must be coordinated with the supply of iron to erythroid precursors. Increased iron supply for erythropoiesis is ensured by the suppression of hepcidin, the iron-regulatory hormone produced by the liver. Low hepcidin levels allow greater absorption of dietary iron and greater mobilization of iron from the stores in the spleen and the liver. The mechanisms coordinating erythropoietic activity with iron delivery are not well understood. We recently identified erythroferrone as a new mediator of hepcidin suppression during stress erythropoiesis1. Erythroferrone (ERFE) is a member of the C1q/TNF-related protein (CTRP) family of metabolic mediators. ERFE is produced in response to EPO by erythroblasts of the bone marrow and spleen of mice. The induction of ERFE by EPO was dependent on Jak2/Stat5 signaling. Ex vivo treatment of human erythroblasts with EPO also resulted in a dramatic induction of ERFE expression. The essential role of ERFE in acute hepcidin suppression by erythropoiesis was demonstrated in ERFE-deficient mice. In contrast to wild-type mice which suppressed hepcidin ~10-fold within hours after hemorrhage or erythropoietin injection, no hepcidin suppression was observed in ERFE knockout mice within 24 h. As a consequence, ERFE-deficient mice exhibited delayed recovery of hemoglobin after hemorrhage or severe inflammation. Treatment of mice or hepatocytes with recombinant ERFE protein confirmed the hepcidin-suppressive activity of the protein. It remains to be seen whether administration of ERFE protein would be useful for the treatment of anemia of inflammation mediated by elevated hepcidin. In iron-loading anemias including β-thalassemia, hepcidin is chronically suppressed by the exuberant but ineffective erythropoietic activity. This is the cause of iron overload in untransfused thalassemia patients and may contribute to iron loading even in transfused patients. We found that ERFE expression is greatly increased in the bone marrow and spleen of mice with β-thalassemia intermedia (th3 model). Transgenic ablation of ERFE in th3 mice normalized hepcidin and partially corrected their iron overload. Although human studies of the role of ERFE in health and disease are clearly needed, ERFE is a promising candidate for the pathological suppressor of hepcidin in anemias with ineffective erythropoiesis. References: 1. Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014; 46: 678-684. Disclosures Nemeth: Intrinsic LifeSciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Merganser Biotech: Equity Ownership. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Keryx Pharma: Consultancy; Merganser Biotech: Consultancy, Equity Ownership.

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Sangkhae, Veena, Vivian Yu, Richard Coffey, Tomas Ganz, and Elizabeta Nemeth. "Erythroferrone Modulates Iron Distribution for Fetal Erythropoiesis." Blood 138, Supplement 1 (November 5, 2021): 757. http://dx.doi.org/10.1182/blood-2021-153902.

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Abstract Erythroferrone (ERFE) is an erythroblast-derived regulator of iron metabolism, and its production increases during stress erythropoiesis. ERFE decreases expression of the iron-regulatory hormone hepcidin to enhance iron availability for erythropoiesis 1. Pregnancy requires a substantial increase in iron availability to sustain a dramatic increase in maternal RBC volume and support fetal development. Whether maternal or fetal ERFE plays a role in regulating iron homeostasis during pregnancy is unknown. In humans, maternal ERFE concentrations were elevated in anemic pregnancies at mid gestation and delivery 2. To define the role of ERFE during iron-replete or iron-deficient pregnancy, we utilized Erfe transgenic (ETg) 3 and Erfe knockout (EKO) 1 mice. Maternal iron status of ETg, WT and EKO mice was altered by placing animals on adequate iron (100ppm) or low iron (4ppm) diet 2 weeks prior to and throughout pregnancy. ETg and WT dams were mated with WT sires to generate ETg and WT embryos while EKO dams were mated with EKO sires to generate EKO embryos. Analysis was performed at embryonic day 18.5. To examine the effect of pregnancy on ERFE expression, we compared non-pregnant females to WT dams at E18.5. Serum ERFE was mildly elevated from 0.01 to 0.2 ng/mL in iron-replete dams, but substantially elevated from 0.01 to 3.1 ng/mL in iron-deficient dams, similarly to human pregnancy 2. We next assessed iron and hematological parameters in pregnant dams with different Erfe genotypes. Under iron-replete conditions, all three groups had similar serum hepcidin, serum iron and hemoglobin concentrations, but ETg dams had 3-fold higher liver iron than WT and EKO dams, presumably because they are mildly iron-overloaded before pregnancy. On iron-deficient diet, maternal hepcidin was decreased in all three genotypes but more so in ETg dams; however, all three Erfe genotypes had similarly depleted liver iron stores, hypoferremia and anemia. MCV was the only parameter that was decreased in EKO compared to WT dams under both iron conditions. Overall, maternal ERFE played a minor role in regulation of maternal erythropoiesis and iron homeostasis, with the lack of ERFE resulting in smaller RBCs but not anemia. Among embryos, we observed a significant effect of Erfe genotype on embryo hepcidin. ETg embryos had significantly lower liver hepcidin compared to WT embryos under both iron-replete and iron-deficient conditions. Conversely, Erfe KO embryos had higher hepcidin compared to WTs under iron-deficient conditions, indicating that embryo ERFE regulates embryo hepcidin during pregnancy. Under iron-replete conditions however, all three embryo genotypes had similar hematologic parameters, and embryo liver iron was dependent on maternal iron levels, with both ETg and WT embryos from ETg dams having increased liver iron concentrations, indicating that embryo ERFE does not regulate placental iron transfer. Under iron-deficient conditions, there was no difference between ETg and WT embryos in hematological or iron parameters, and both genotypes developed iron deficiency and anemia. However, Erfe KO embryos, which had elevated hepcidin, had maldistribution of iron and worse anemia. EKO embryo liver iron concentrations were 6-fold higher compared to WT iron-deficient embryos, whereas hemoglobin was significantly decreased compared to WT iron-deficient embryos. These findings indicate that under iron-limiting conditions, embryo ERFE is important for the suppression of embryo hepcidin to ensure iron redistribution for embryo erythropoiesis. In summary, during iron replete pregnancy, ERFE plays a minor role in maternal and fetal iron homeostasis and erythropoiesis. However, in response to iron-deficiency anemia during pregnancy, ERFE is important for the redistribution of iron within the embryo to support embryo erythropoiesis. 1Kautz L et al, Nat Genet, 2014 2Delaney K et al, Curr Dev Nutr, 2020 3Coffey R et al, Blood, 2020 Disclosures Ganz: Ambys: Consultancy; Sierra Oncology: Consultancy, Research Funding; Rockwell: Consultancy; Pharmacosmos: Consultancy; Ionis: Consultancy; Protagonist: Consultancy; Intrinsic LifeSciences: Consultancy; RallyBio: Consultancy; Silence Therapeutics: Consultancy; Silarus Pharma: Consultancy; Alnylam: Consultancy; American Regent: Consultancy; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenecaFibrogen: Consultancy; Global Blood Therapeutics: Consultancy; Gossamer Bio: Consultancy; Akebia: Consultancy, Honoraria. Nemeth: Silarus Pharma: Consultancy; Intrinsic LifeSciences: Consultancy; Protagonist: Consultancy; Vifor: Consultancy; Ionis: Consultancy.

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Arezes, Joao, Niall Foy, Susan Benard, Anagha Sawant, May S. Tam, Zachary Maben, Kirsty McHugh, et al. "Antibodies Against the Erythroferrone N-Terminal Domain Prevent Hepcidin Suppression and Ameliorate Murine Thalassemia." Blood 134, Supplement_1 (November 13, 2019): 964. http://dx.doi.org/10.1182/blood-2019-130246.

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Erythroferrone (Erfe) is produced by erythroblasts in response to erythropoietin (EPO) and acts in the liver to prevent hepcidin stimulation by BMP6. Hepcidin suppression allows for the mobilization of iron to the bone marrow for the production of red blood cells. Aberrantly high circulating Erfe levels in conditions of stress erythropoiesis, such as in patients with β-thalassemia, promote the tissue iron accumulation that decisively contributes to morbidity in these patients. Here we developed neutralizing antibodies against Erfe to prevent hepcidin suppression and correct the iron loading phenotype in a mouse model of β-thalassemia (Hbb Th3/+ mice) and used these antibodies as tools to further characterize Erfe's mechanism of action. We demonstrate that Erfe binds to BMP6 with low nanomolar affinity, but also binds BMP2 and BMP4 with lower affinities. We further show that BMP6 binds the N-terminal domain of ERFE. This domain in itself was sufficient to cause hepcidin suppression in Huh7 hepatoma cells and in vivo in wildtype mice. Concurrently, anti-Erfe antibodies targeting the N-terminal domain prevented hepcidin suppression in Erfe-treated Huh7 cells and in EPO-treated mice. Crystal structure of the antibodies in contact with an N-terminal peptide of Erfe demonstrated critical contacts in the Erfe N-terminal domain imparting antibody selectivity to human and murine protein. Finally, we tested these antibodies in vivo in a mouse model of thalassemia. We observed a decrease in serum and liver iron in antibody-treated Hbb Th3/+ mice. In addition, treatment with anti-Erfe antibodies increased the number of red blood cells, hemoglobin concentration and hematocrit, while decreasing the number of reticulocytes and the red cell distribution width. These changes were more pronounced when mice are treated for eight weeks. Anti-Erfe treatment caused an increase in hepatic hepcidin mRNA expression, red blood cells, hemoglobin and hematocrit, while reticulocytes levels were lower and peripheral red cell lifespan was increased. In summary, we demonstrate that antibodies targeting the N-terminal domain of Erfe constitute a potential therapeutic tool for iron-loading anemias. Disclosures Arezes: UCB: Employment. Foy:Pfizer Inc.: Employment. Benard:pfizer: Employment. Sawant:Pfizer Inc.: Employment. Tam:Pfizer Inc.: Employment. Maben:Pfizer Inc.: Employment. LaVallie:Pfizer Inc.: Employment. Cunningham:Pfizer Inc.: Employment. Lambert:Pfizer Inc.: Employment. Pittman:Pfizer Inc.: Employment. Murphy:Pfizer Inc.: Employment. Draper:Pfizer: Research Funding. Jasuja:Pfizer Inc.: Employment. Drakesmith:Pfizer: Consultancy, Research Funding; Kymab: Other: Scientific Advistory; La Jolla Pharmaceutical: Research Funding.

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Coffey, Richard, Grace Jung, Elizabeta Nemeth, and Tomas Ganz. "Transgenic Mice Overexpressing Erythroferrone, a Novel Erythrokine, Develop Iron Overload and Multi-Organ Iron-Independent Abnormalities." Blood 136, Supplement 1 (November 5, 2020): 12. http://dx.doi.org/10.1182/blood-2020-141677.

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Erythroferrone (ERFE) is a hormone secreted by erythroblasts in response to endogenous or exogenous erythropoietic stimuli. ERFE suppresses the production of the iron-regulatory hormone hepcidin by hepatocytes, thereby allowing for increased iron absorption and iron mobilization to support intensified erythropoiesis. In disorders of ineffective erythropoiesis, such as β-thalassemia or congenital dyserythropoietic anemias, chronic suppression of hepcidin results in excessive iron absorption, toxic iron accumulation and a range of systemic manifestations, some of which appear unrelated to iron overload. Recent evidence suggests that ERFE is a ligand trap for select bone morphogenetic proteins (BMPs). BMPs regulate iron homeostasis, but also modulate diverse physiologic processes including embryonic development, kidney growth, and bone homeostasis. Existing mouse models of β-thalassemia used to study the effects of elevated ERFE in vivo are confounded by chronic anemia and hemolysis, complicating attribution of observed phenotypes directly to the action of ERFE. Additionally, serum ERFE levels in these mouse models are much lower than those measured in human patients with β-thalassemia, resulting in a potential underestimation of the pathophysiologic effects of elevated ERFE. To determine the specific effect of elevated ERFE levels in vivo, we generated multiple lines of novel transgenic mice that selectively overexpress graded levels of Erfe in erythroid cells. As expected, Erfe transgenic mice, relative to wild-type littermates, displayed a dose-dependent phenotype of liver iron loading with inappropriately low hepcidin expression. At 6 weeks of age liver nonheme iron levels in transgenic mice ranged from ~2 times that of wild-type littermates, in the lowest expressing line, to ~4 times that of wild-type littermates in the highest-expressing line (line H mice). However, elevated Erfe expression did not consistently alter expression of the BMP target genes Id1 or Smad7 in either the liver or bone marrow. Line-H transgenic mice had increased hemoglobin, hematocrit, mean corpuscular volume, and serum iron suggesting that elevated ERFE levels promoted erythropoiesis, at least in part, by suppressing hepcidin and mobilizing more iron, generating a phenotype similar to mouse models of hereditary hemochromatosis. We also observed phenotypic features that appeared unrelated to iron excess. Line-H breeding diverged from the expected mendelian inheritance ratio of 50% transgenic pups for male mice at weaning age, yielding 37% transgenic pups (N = 108, p =0.0035). Transgenic mice from line-H also had lower body weights and reduced kidney size, accompanied by higher serum urea levels. Additionally, approximately a third of line-H transgenic mice displayed an unusual behavior characterized by repetitive circling and an impaired righting reflex, suggesting vestibular dysfunction. These findings of stunted growth, renal impairment and behavioral abnormalities raise the possibility that elevated ERFE levels may exert iron-independent adverse effects in congenital anemias with ineffective erythropoiesis and in β-thalassemia, perhaps by inhibiting BMP-dependent developmental signals. Future studies using the graded expression of the Erfe-transgene combined with mouse models of dyserythropoiesis will facilitate analysis of the contribution of varying levels of ERFE to the pathophysiology of ineffective erythropoiesis and lay the foundation for pharmacologically targeting ERFE for the amelioration of the hematologic and nonhematologic manifestations of anemias with ineffective erythropoiesis. Disclosures Nemeth: Vifor: Consultancy; Protagonist: Consultancy; Ionis Pharmaceuticals: Consultancy; Silarus Therapeutics: Current equity holder in private company; Intrinsic LifeSciences: Current equity holder in private company. Ganz:Disc Medicine: Consultancy; Silarus Therapeutics: Current equity holder in private company; Intrinsic LifeSciences: Current equity holder in private company; Ambys: Consultancy; Sierra Oncology: Consultancy; Rockwell: Consultancy; Gossamer Bio: Consultancy; American Regent: Consultancy; Global Blood Therapeutics: Consultancy; Astellas: Consultancy; Akebia: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy.

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Delaney, Katherine M., Ronnie Guillet, Eva K. Pressman, Tomas Ganz, Elizabeta Nemeth, and Kimberly O. O'Brien. "Serum Erythroferrone During Pregnancy Is Related to Erythropoietin but Does Not Predict the Risk of Anemia." Journal of Nutrition 151, no. 7 (May 19, 2021): 1824–33. http://dx.doi.org/10.1093/jn/nxab093.

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ABSTRACT Background Maintaining adequate iron status during pregnancy is important for the mother and her developing fetus. Iron homeostasis is influenced by 3 regulatory hormones: erythropoietin (EPO), hepcidin, and erythroferrone (ERFE). To date, normative data on ERFE across pregnancy and its relations to other hormones and iron status indicators are limited. Objectives The objective of this study was to characterize maternal ERFE across pregnancy and at delivery and evaluate the utility of hepcidin, ERFE, and EPO in identifying women with increased iron needs. Methods ERFE was measured in extant serum samples collected from 2 longitudinal cohorts composed of women carrying multiple fetuses (n = 79) and pregnant adolescents (n = 218) at midgestation (∼26 wk) and delivery (∼39 wk). Receiver operating characteristic curves were generated to characterize the predictive ability of serum ERFE, hepcidin, and EPO and their ratios to identify women at increased risk of iron deficiency and anemia. Results In these pregnant women, mean ERFE was 0.48 ng/mL at both ∼25 wk of gestation and at delivery. ERFE was positively associated with EPO at midgestation (β = 0.14, P = 0.002, n = 202) and delivery (β = 0.12, P < 0.001, n = 225) but was not significantly associated with maternal hepcidin at any time point surveyed. Of all hormones measured at midgestation and delivery, EPO was best able to identify women with anemia (AUC: 0.86 and 0.75, respectively) and depleted iron stores (AUC: 0.77 and 0.84), whereas the hepcidin-to-EPO ratio was best able to identify women with iron deficiency anemia (AUC: 0.85 and 0.84). Conclusions Maternal ERFE was significantly associated with EPO but was not able to identify women with gestational iron deficiency. At term, the hepcidin-to-EPO ratio, an index that accounts for both iron status and erythropoietic demand, and EPO were the strongest indicators of maternal iron deficiency and anemia. This trial was registered at clinicaltrials.gov as NCT04517734 (https://clinicaltrials.gov/ct2/show/NCT04517734).

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Sardo, Ugo, Prunelle Perrier, Benjamin Billore, Kevin Cormier, and Leon C. Kautz. "Evidence for an Alternative Mechanism Suppressing Hepcidin during the Recovery from Hemorrhage-Induced Anemia." Blood 132, Supplement 1 (November 29, 2018): 1047. http://dx.doi.org/10.1182/blood-2018-99-118647.

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Abstract Introduction The liver-produced hormone hepcidin regulates the body iron stores. Its expression is induced by iron and inflammatory cytokines but repressed by the erythroid regulator erythroferrone (ERFE) when erythropoietic activity intensifies during anemia. Although Erfe-deficient mice fail to appropriately suppress hepcidin during the first 24h following hemorrhage, these mice still recover from anemia with a few days delay suggesting that another mechanism compensates for the absence of ERFE. We therefore decided to study the kinetic of hepcidin during the recovery from anemia induced by bleeding in Erfe-deficient mice. Material and methods Six week-old C57BL/6 WT and Erfe-deficient mice were phlebotomized (500 μL) and analyzed 1, 2, 3, 4, 5 and 6 days after phlebotomy until full recovery. Results Liver hepcidin mRNA expression was suppressed 5-fold one to five days after phlebotomy in WT mice. In contrast with the sustained inhibition of hepcidin, serum ERFE concentration progressively decreased after 24 hours to reach its baseline at day 4. Interestingly, although hepcidin levels were unchanged after 24 hours, Erfe-deficient exhibited significantly reduced hepcidin levels after 48 hours. Hepcidin mRNA and protein levels were comparable to those of WT mice 2 to 5 days after phlebotomy. Interestingly, the repression of hepcidin occurred without any change in phosphorylation of the effectors Smadd1/5/8 and in hepatic expression of the BMP/SMAD target genes Atoh8, Smad7 and Id1. Similarly, mRNA expression of the proposed negative regulators of hepcidin Gdf15, Twsg1 and Gdf11 was not increased in the spleen and the bone marrow of phlebotomized mice compared to control mice. Finally, disruption of the erythroid compartment by irradiation or injection of carboplatin prevented the suppression of hepcidin in WT and Erfe-deficient mice. Conclusion An alternative mechanism regulates hepcidin independently of iron and ERFE during stress erythropoiesis. Our data suggest that a second yet unknown erythroid regulator of hepcidin may exist. Disclosures No relevant conflicts of interest to declare.

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Arezes, João, Niall Foy, Kirsty McHugh, Anagha Sawant, Doris Quinkert, Virginie Terraube, Alette Brinth, et al. "Erythroferrone inhibits the induction of hepcidin by BMP6." Blood 132, no. 14 (October 4, 2018): 1473–77. http://dx.doi.org/10.1182/blood-2018-06-857995.

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Kautz, Léon, Grace Jung, Elizabeta Nemeth, and Tomas Ganz. "Erythroferrone contributes to recovery from anemia of inflammation." Blood 124, no. 16 (October 16, 2014): 2569–74. http://dx.doi.org/10.1182/blood-2014-06-584607.

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Silvestri, Laura, Antonella Nai, Alessandro Campanella, Irene Artuso, Jessica Bordini, and Clara Camaschella. "Inactivation of Tmprss6 Hampers Hepcidin Inhibition By Erythroferrone through Upregulation of the BMP-SMAD Pathway." Blood 126, no. 23 (December 3, 2015): 408. http://dx.doi.org/10.1182/blood.v126.23.408.408.

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Abstract Introduction Erythroferrone (ERFE), a member of the C1q-TNF protein family produced by erythropoietin (EPO)-stimulated erythroid cells, has been recently identified as the erythroid regulator that suppresses hepcidin (Kautz et al., 2014). In the liver, the main hepcidin inhibitor is TMPRSS6, the only known in vivo inhibitor of the BMP-SMAD pathway since its inactivation causes Iron Refractory Iron Deficiency Anemia (IRIDA) (Finberg et al., 2008), a genetic disorder due to inappropriately high hepcidin. We have previously demonstrated that inactivation of Tmprss6 in thalassemia mice rescues iron overload and ameliorate anemia by increasing hepcidin, notwithstanding high Epo (Nai et al., 2012) and Erfe (Silvestri et al., ASH Meeting 2014) thus suggesting that Tmprss6 is indispensable for hepcidin inhibition by the erythroid regulator(s). Methods To analyze BM and spleen erythroid differentiation, Ter119+ cells were separated according to Forward Scatter (FSC) value and Cd44 expression, as previously described (Liu et al., 2013). Expression of Erfe, Epo, hepcidin and BMP-SMAD target genes were evaluated by qRT-PCR and iron parameters by standard methods (Pagani et al., 2011). We have analyzed different animal models after a single (200U) EPO injection: 1) Tmprss6 KO mice and wild type littermates fed an iron balanced (IB) and iron deficient (ID), diet; 2) wild type mice with activated BMP-SMAD pathway by iron dextran (1g/kg) treatment; 3) Tmprss6 KO animals with the BMP-SMAD pathway inhibited by 12.5 μg/g dorsomorphin. Both males and females mice were analyzed at 8-10 weeks of age and sacrificed 15 hours after EPO treatment. Results EPO administration increases bone marrow (BM) erythroid precursors in all mice models. In the spleen erythroid precursors are not further upregulated by EPO in ID and Tmprss6 KO mice, since already high in basal conditions likely due to stress erythropoiesis. Erfe expression is upregulated in basal conditions in BM and spleen of ID and Tmprss6 KO mice, which have high serum Epo levels, and is further increased by EPO treatment in all models. As expected, hepcidin is strongly reduced in ID animals, whereas it is high in Tmprss6 KO mice. EPO injection strongly inhibits hepcidin both in IB and ID mice but not in Tmprss6 KO animals, notwithstanding the upregulation of Erfe. This suggests that lack of Tmprss6 impairs the Erfe-mediated hepcidin inhibition. To evaluate the contribution of Tmprss6 and the BMP signaling to Erfe function, we modulated the BMP pathway before EPO challenge. We activated the signaling by means of iron dextran injection in wild type mice and we inhibited the hyperactive pathway of Tmprss6 KO animals by using the BMP receptor inhibitor dorsomorphin. Neither iron dextran injection nor dorsomorphin treatment impairs Erfe activation by EPO that equals that observed in saline treated animals. In iron loaded mice with hyperactive BMP signaling, hepcidin was not inhibited by Erfe. Dorsomorphin treatment in Tmprss6 KO animals rescues the hepcidin responsiveness to Erfe. Conclusions We confirm that the BMP-SMAD pathway is dispensable for Erfe-mediated hepcidin inhibition since Erfe decreases hepcidin in ID, when the pathway is suppressed. However, activation of the BMP-SMAD pathway consequent to iron loading or to the loss of Tmprss6 hampers the hepcidin downregulation by Erfe, suggesting that the Tmprss6 function, and not Tmprss6 per se, is essential to facilitate the Erfe-dependent hepcidin inhibition by blunting the BMP-SMAD signaling. Disclosures No relevant conflicts of interest to declare.

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Dziembowska, Inga, Małgorzata Wójcik, Jakub Bukowski, and Ewa Żekanowska. "Physical Training Increases Erythroferrone Levels in Men." Biology 10, no. 11 (November 21, 2021): 1215. http://dx.doi.org/10.3390/biology10111215.

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Intense physical activity contributes to an increased demand for red blood cells, which transport oxygen to working muscles. The purpose of this study was to assess the concentration of erythroferrone (ERFE), the novel marker of erythroid activity in athletes, during the beginning of their training season. The study group consisted of 39 athletes aged 23.24 ± 3.77 years. The study was carried out during the athletes’ preparatory period of the training cycle. The control group consisted of 34 healthy men aged 22.33 ± 2.77 years. The erythropoietic activity was evaluated by determining athletes’ concentrations of erythropoietin (EPO) and erythroferrone (ERFE). The level of physical activity was assessed using the International Physical Activity Questionnaire (IPAQ). In the athletes’ group, we observed higher concentrations of EPO (Me = 12.65 mIU/mL) and ERFE (40.00 pg/mL) compared to the control group (EPO: Me = 5.74 mIU/ml, p = 0.001; ERFE: Me = 25.50 pg/mL, p = 0.0034). The average intensity of physical exercise significantly differentiated the participants as far as EPO and ERFE concentrations. These results suggest that intense physical activity, at least at the beginning of the training season, may stimulate EPO production, which increases ERFE release. This seems to be an adaptative mechanism that provides adequate iron for enhanced erythropoiesis.

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Diepeveen, Laura, Rian Roelofs, Nicolai Grebenchtchikov, Rachel van Swelm, Leon Kautz, and Dorine Swinkels. "Differentiating iron-loading anemias using a newly developed and analytically validated ELISA for human serum erythroferrone." PLOS ONE 16, no. 7 (July 20, 2021): e0254851. http://dx.doi.org/10.1371/journal.pone.0254851.

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Erythroferrone (ERFE), the erythroid regulator of iron metabolism, inhibits hepcidin to increase iron availability for erythropoiesis. ERFE plays a pathological role during ineffective erythropoiesis as occurs in X-linked sideroblastic anemia (XLSA) and β-thalassemia. Its measurement might serve as an indicator of severity for these diseases. However, for reliable quantification of ERFE analytical characterization is indispensable to determine the assay’s limitations and define proper methodology. We developed a sandwich ELISA for human serum ERFE using polyclonal antibodies and report its extensive analytical validation. This new assay showed, for the first time, the differentiation of XLSA and β-thalassemia major patients from healthy controls (p = 0.03) and from each other (p<0.01), showing the assay provides biological plausible results. Despite poor dilution linearity, parallelism and recovery in patient serum matrix, which indicated presence of a matrix effect and/or different immunoreactivity of the antibodies to the recombinant standard and the endogenous analyte, our assay correlated well with two other existing ERFE ELISAs (both R2 = 0.83). Nevertheless, employment of one optimal dilution of all serum samples is warranted to obtain reliable results. When adequately performed, the assay can be used to further unravel the human erythropoiesis-hepcidin-iron axis in various disorders and assess the added diagnostic value of ERFE.

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Mossner, Maximilian, Alexandra Stoehr, Johann-Christoph Jann, Florian Nolte, Verena Nowak, Julia Oblaender, Jovita Pressler, et al. "Erythroferrone (ERFE) Is Selectively Expressed in Human CD71+ Erythroprogenitor Cells and Deregulated Overexpression Is Associated with a Favorable Outcome in Low Risk Myelodysplastic Syndrome (MDS)." Blood 126, no. 23 (December 3, 2015): 2859. http://dx.doi.org/10.1182/blood.v126.23.2859.2859.

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Abstract Introduction Recently, Erythroferrone (ERFE) was discovered as a new regulator of hepcidin in the context of hematopoietic stress and erythropoietin (EPO) stimulation (Kautz et al., Nature Genetics 2014). ERFEhas been shown to be expressed by erythroprogenitor cells of the bone marrow in response to increased erythroid activity induced by phlebotomy, EPO treatment or simulation of infectious situations in mice. It induces increased iron availability by downregulation of hepcidin in the liver and therefore represents an important new factor in iron homeostasis to be explored as a potential diagnostic or therapeutic target in the context of anemia and iron overload. Myelodysplastic Syndromes (MDS) are a group of heterogeneous malignant hematologic diseases characterized by inefficient hematopoiesis, severe anemia and deregulated iron homeostasis. In order to determine the specific role of ERFE in MDS, we analyzed the gene expression of ERFE in different hematopoietic compartments of MDS patients and healthy controls and correlated the differential expression data with clinical parameters and survival. Methods CD71+ erythroprogenitor cells (n=198 samples) were immunomagnetically purified from mononuclear bone marrow (BM) cells of a total of n=148 MDS and n=18 sAML patients. Chronological samples were available in n=21 cases. For controls, CD71+ BM cells were analyzed from n=35 healthy donors. In addition to CD71+ cells, CD61+, CD15+ , CD34+, selected from BM, as well as CD3+ selected peripheral blood (PB) cells were immunomagnetically collected from three MDS patients as well as two healthy young and two healthy old volunteers. After total RNA extraction using the AllPrep DNA/RNA Mini kit (Qiagen), cDNA was transcribed from RNA via Quantitect cDNA synthesis kit (Qiagen). Subsequently, ERFE expression was quantified from cDNA by quantitative PCR. Results In comparative expression analyses of different hematopoietic BM progenitor fractions (CD34+, CD15+, CD61+ and CD71+), ERFE was almost exclusively expressed in the erythropoietic CD71+ compartment. ERFE expression profiles in the CD71+ subset revealed a highly significant overexpression of this gene in MDS IPSS-low/int-1-risk (fold change (FC)=4.3, p<0.0001), IPSS-int-2/high-risk (FC=6.23, p<0.0001) and sAML (FC=6.69, p<0.0001) relative to healthy controls. ERFE expression profiles in MDS and sAML did not correlate with clinical laboratory parameters such as hemoglobin, EPO levels, ferritin, cobalamine, folic acid, transferrin, transferrin saturation, soluble transferrin receptor, reticulocytes, zinc protoporphyrin and lactate dehydrogenase. A negative correlation was observable for c-reactive protein levels (p=0.0053, Spearman r=-0.29) suggesting a possible link between an inflammatory environment and ERFE regulation. In exemplary chronological time course samples, ERFE expression was upregulated subsequent to clinical therapies such as 5-Azacytidine or Lenalidomide. Interestingly, in the total cohort of MDS patients with survival data follow up (n=90), low ERFE expression was associated with a significantly worse survival than high ERFE expression (median survival 2.1 years versus not reached, HR: 4.4, p=0.0007). This observation was even more pronounced in the subgroup analysis of MDS IPSS low/int-1 risk patients (n=54, median survival 2.1 years versus not reached, HR: 22, p<0.0001). Conclusion The observed highly aberrant overexpression of ERFE in CD71+ erythropoietic progenitor cells suggests an important role for this gene in the dysfunctional erythropoiesis of MDS. The observation of a correlation between ERFE expression and survival, especially in low risk MDS patients with no apparent coherence to other established clinical markers warrants further pursuit of ERFE expression profiles in CD71+ BM cells of MDS patients as a possible independent prognostic marker. Moreover, aberrant levels of ERFE could provide a promising target for novel therapeutic avenues that mechanistically address dysfunctional erythropoiesis in MDS. Disclosures No relevant conflicts of interest to declare.

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Oarbeascoa, Gillen, Sara Redondo, Maria Jose Morán-Jiménez, Amalia Domingo, Cristina Muñoz-Linares, Maria Isabel Moreno-Carralero, Jose Maria Bellon, Juan Francisco del Campo Rincon, Jose Luis Díez-Martín, and Patricia Font. "Hepcidin and Erythroferrone in the Anemia of Low-Risk Myelodysplastic Syndromes." Blood 132, Supplement 1 (November 29, 2018): 3085. http://dx.doi.org/10.1182/blood-2018-99-116992.

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Abstract BACKGROUND: Anemia is the most common manifestation of low-risk myelodysplastic syndromes (MDS). Iron-overload in MDS can occur before transfusion dependence in the context of ineffective erythropoiesis. Significantly lower hepcidin levels have been described in patients with sideroblastic refractory anemia compared to higher risk MDS, promoting inadequate iron absorption that leads to higher iron overload. Erythroferrone (ERFE) is a hormone that stimulates erythropoiesis and regulates iron homeostasis; in physiological conditions, is stimulated by erythropoietin and increases iron absorption inhibiting hepcidin. There are no studies describing the activity of ERFE in MDS. The objective of this study was to describe the relationship among hepcidin, ERFE and iron overload in 31 patients with low-risk MDS. METHODS: 50 samples were analized, 31 from patients (16 males, 17 females) with low-risk MDS: 10 low IPSS-R and 21 very-low IPSS-R; and 19 from healthy controls. 13 patients showed severe anemia with transfusion dependence, 4 patients received only erythropoiesis stimulating agents (ESA) and 14 patients did not receive any treatment for the anemia. Patient characteristics are summarized in table 1. Hepcidin levels were measured using the DRG Hepcidin 25 (bioactive) HS ELISA Kit (DRG Diagnostics GmbH), and ERFE was measured with the FAM132B (Human) OKEH02395 ELISA kit (Aviva Systems). For the analysis, two groups of patients were considered: 13 with severe and transfusion dependent anemia and 18 with mild/moderate anemia. RESULTS: Patients with severe anemia showed higher serum ferritin levels (median 2143ng/mL vs 204ng/mL, p<0.001) compared to patients without transfusion dependence. Hepcidin levels were significantly higher in patients with transfusion dependent anemia (mean 59.85 vs 16.11ng/mL, p=0.001) compared to patients with transfusion independence, and were also higher in these last patients compared to healthy controls (mean 16.11 vs 10.6ng/mL, p<0.001). Regarding ERFE, patients with transfusion dependent anemia showed significantly higher ERFE levels (mean 281.92 vs. 62.83pg/mL, p=0.016) than patients with mild/moderate anemia. However, there were no significant differences between patients with mild/moderate anemia and healthy controls. There was no correlation between hepcidin and ERFE levels (p=0.46). CONCLUSIONS: To the best of our knowledge, this is the first simultaneous analysis of hepcidine and ERFE in MDS. Patients with severe anemia showed significantly higher ERFE levels compared to those with moderate anemia, suggesting a higher erythropoietic stimulus. Patients with severe anemia showed significantly superior hepcidin levels, hindering iron absorption in situations of massive iron overload. Accordingly, ERFE did not show negative correlation with hepcidin in either cohort, supporting the abnormal iron metabolism in MDS. Larger studies are required to define the relationship between hepcidin and ERFE in low-risk MDS. Disclosures No relevant conflicts of interest to declare.

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Bondu, Sabrina, Anne-Sophie Alary, Carine Lefèvre, Alexandre Houy, Grace Jung, Thibaud Lefebvre, David Rombaut, et al. "A variant erythroferrone disrupts iron homeostasis inSF3B1-mutated myelodysplastic syndrome." Science Translational Medicine 11, no. 500 (July 10, 2019): eaav5467. http://dx.doi.org/10.1126/scitranslmed.aav5467.

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Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in theSF3B1splicing factor gene. Patients with MDS withSF3B1mutations often accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for erythropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternativeERFEtranscript in patients with MDS with theSF3B1mutation. Induction of thisERFEtranscript in primarySF3B1-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with anSF3B1gene mutation than in patients withSF3B1wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients withSF3B1-mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variantERFEtranscript that was restricted toSF3B1-mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.

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Mossner, Maximilian, Alexandra Stöhr, Florian Nolte, Johann-Christoph Jann, Stephanie Fey, Verena Nowak, Julia Obländer, et al. "Gene Expression of the Erythroid Regulator Erythroferrone (ERFE) is Highly Deregulated in CD71+ Erythroprogenitor Cells of Patients with Myelodysplastic Syndromes and Demonstrates Prognostic Relevance." Blood 124, no. 21 (December 6, 2014): 4620. http://dx.doi.org/10.1182/blood.v124.21.4620.4620.

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Abstract Introduction Myelodysplastic Syndromes (MDS) are clonal hematologic diseases that are characterized by inefficient hematopoiesis, severe anemia and resulting deregulated iron homeostasis. Apart from supportive therapy with red blood cell transfusions some MDS patients with anemia respond to treatment with erythropoiesis stimulating agents such as Erythropoietin (EPO). However, the majority of these patients also become refractory to EPO treatment during the course of disease, suggesting a dysfunctional regulation of erythropoiesis downstream of EPO signaling in MDS. Most recently, a crucial erythroid regulator of iron metabolism named Erythroferrone (ERFE) was newly discovered, which is selectively produced by bone marrow (BM) erythroprogenitor cells during hematopoietic stress and EPO stimulation (Kautz et al. ASH plenary session 2013 and Kautz et al., Nature Genetics 2014). Aberrant expression of ERFE has been shown to directly result in critical impairment of erythropoiesis. We therefore sought to examine the role of ERFEexpression in CD71+ erythroprogenitor cells derived from patients with MDS and secondary acute myeloid leukemia (sAML). Methods CD71+ erythroprogenitor cells were immunomagnetically isolated from ficollized mononuclear BM cells of patients suffering from MDS (n=86, IPSS-low/int-1-risk n=69, IPSS-int-2/high-risk n=17), sAML (n=18) and age-matched healthy donors (n=17). In addition to CD71+ cells, CD34+, CD61+, CD15+ selected BM as well as CD3+ selected peripheral blood (PB) cells were immunomagnetically collected from three MDS patients as well as two healthy young and two healthy old donors. After total RNA was extracted using the AllPrep DNA/RNA Mini kit (Qiagen), cDNA was transcribed from RNA via Quantitect cDNA synthesis kit (Qiagen). Subsequently, ERFE expression was quantified from cDNA by quantitative PCR and normalized to corresponding GPIhousekeeping gene expression levels. Patient follow up (FU) data was available for n=55 MDS and n=14 sAML samples. Results Analysis of ERFE expression in CD34+, CD15+, CD61+ and CD71+ BM as well as CD3+ and unselected mononuclear PB cells from MDS patients and healthy donors revealed almost exclusive expression of ERFE in CD71+ erythroprogenitor cells irrespective of disease state. Our analysis of ERFE expression profiles in this specific cell subset revealed a highly significant overexpression of this gene in MDS IPSS-low/int-1-risk (fold change (FC)=4.1, p<0.0001), IPSS-int-2/high-risk (FC=4.6, p=0.0003) and sAML (FC=6.5, p<0.0001) relative to age-matched healthy controls. Despite this marked profile of aberrantly regulated ERFE we identified a distinct fraction of patients with expression levels similar or even lower than those measured in healthy donors in 20% (11/55) and 36% (5/14) of analyzed MDS and sAML cases with FU. Univariate analysis revealed that low abundance of CD71+ ERFE transcripts was significantly associated with inferior overall survival (OS) in MDS patients (median survival 1.7 years vs. not reached, p=0.0066) and also sAML (median survival 0.1 vs. 0.8 years, p=0.031). Conclusion The recent identification of the novel key regulatory gene ERFE in mouse models has greatly improved the understanding of the dynamic regulation of erythropoiesis. Our observation of almost exclusive ERFE expression in human BM erythroprogenitor cells further underlines its important role in human erythropoietic regulation both in healthy and myelodysplastic hematopoiesis. Moreover, strong upregulation of erythropoiesis stimulating ERFE in a large proportion of MDS patients usually suffering from anemia likely indicates its involvement in perturbed mechanisms of feedback signaling in MDS erythropoiesis. Pending integration with further clinical data, the current observation of significantly inferior survival probability for MDS and sAML patients with low ERFE expression levels indicates the potentially important biologic and clinical relevance of this novel regulatory gene in the pathogenesis of MDS. Consequently, aberrant levels of the erythroid hormone ERFEin MDS erythroprogenitor cells might provide a promising target for novel therapeutic avenues that mechanistically address dysfunctional erythropoiesis in MDS. Disclosures Nolte: Celgene Corp., Novartis Pharma: Honoraria, Research Funding.

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Spoto, Kakkar, Lo, Devalaraja, Pizzini, Torino, Leonardis, et al. "Serum Erythroferrone Levels Associate with Mortality and Cardiovascular Events in Hemodialysis and in CKD Patients: A Two Cohorts Study." Journal of Clinical Medicine 8, no. 4 (April 16, 2019): 523. http://dx.doi.org/10.3390/jcm8040523.

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Erythroferrone (ERFE) is a hepcidin inhibitor whose synthesis is stimulated by erythropoietin, which increases iron absorption and mobilization. We studied the association between serum ERFE and mortality and non-fatal cardiovascular (CV) events in a cohort of 1123 hemodialysis patients and in a cohort of 745 stage 1–5 chronic kidney disease (CKD) patients. Erythroferrone was measured by a validated enzyme-linked immunosorbent assay (ELISA). In the hemodialysis cohort, serum ERFE associated directly with erythropoiesis stimulating agents (ESA) dose (p < 0.001) and inversely with serum iron and ferritin (p < 0.001). Erythroferrone associated with the combined outcome in an analysis adjusting for traditional risk factors, factors peculiar to end-stage kidney disease, serum ferritin, inflammation, and nutritional status (HR, hazard ratio, (5 ng/mL increase: 1.04, 95% confidence interval, CI: 1.01–1.08, p = 0.005). Furthermore, treatment with ESA modified the relationship between ERFE and the combined end-point in adjusted analyses (p for the effect modification = 0.018). Similarly, in CKD patients there was a linear increase in the risk for the same outcome in adjusted analyses (HR (2 ng/mL increase): 1.04, 95% CI: 1.0–1.07, p = 0.015). Serum ERFE is associated with mortality and CV events in CKD and in HD patients, and treatment by ESA amplifies the risk for this combined end-point in HD patients.

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Hong, Jianghuai, Jingjing Lai, Xiaoying Chen, Yan Yan, Yanyan Hong, Hailun Ke та Jing Zheng. "The effects of hypoxia-inducible factors-1α and -2α and erythroferrone on hepcidin in patients with chronic kidney disease stages 3–5 and renal anemia". European Journal of Inflammation 20 (січень 2022): 1721727X2211034. http://dx.doi.org/10.1177/1721727x221103468.

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Objective This study aimed to investigate the effects of hypoxia-inducible factor-1α (HIF-1α), hypoxia-inducible factor-2α (HIF-2α), and erythroferrone (ERFE) on hepcidin in patients with chronic kidney disease (CKD) stages 3–5 and renal anemia. Methods A total of 90 patients with CKD stages 3–5 and renal anemia were selected for the study at the Nephrology Department of Fujian Provincial People’s Hospital and divided into three groups, according to CKD stage, while another 30 healthy subjects who underwent a physical examination at the hospital during the same period were selected as the normal group. The serum levels of hepcidin, HIF-1α, HIF-2α, ERFE, and furin were measured using an avidin biotin peroxidase complex enzyme-linked immunosorbent assay to compare the differences between the groups in the related indicators. Results ① Serum HIF-2α, HIF-1α, ERFE, and furin levels increased gradually in the patients with CKD stages 3–5 ( p < 0.05, p < 0.01). ②Simple correlation analysis:Serum hepcidin was positively correlated with HIF-2α, ERFE, and HIF-1α in the CKD patients ( p < 0.01). ③Serum hepcidin was positively correlated with HIF-2α, HIF-1α, and ERFE in the CKD patients injected with erythropoietin (EPO) ( p < 0.01), while serum hepcidin was positively correlated with HIF-2α and HIF-1α ( p < 0.01) in the patients not injected with EPO. ④ Multivariate linear regression analysis showed that HIF-1α, (β = 4.36, p < 0.01), serum ferritin(SF) (β = 0.13, p < 0.01), and HIF-2α (β = 0.66, p < 0.01) were significantly correlated with hepcidin. Conclusion HIF-1α, HIF-2α, and SF are factors which have an effect on hepcidin in patients with CKD stages 3–5 and renal anemia. The increase of HIF-1α, HIF-2α, and ERFE does not seem to inhibit the increase of hepcidin.

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Ruiz Martinez, Marc, Wenbin An, Maria Feola, Tomas Ganz та Yelena Ginzburg. "Additive Effects of Decreased TfR1 and Ablated Erfe Improve Both Ineffective Erythropoiesis and Iron Overload in β-Thalassemic Mice". Blood 132, Supplement 1 (29 листопада 2018): 847. http://dx.doi.org/10.1182/blood-2018-99-119426.

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Abstract Patients with β-thalassemias manifest anemia, ineffective erythropoiesis, extramedullary hematopoiesis, splenomegaly, and systemic iron overload. Even in non-transfusion dependent patients, iron overload in β-thalassemia develops because of increased intestinal iron absorption, leading to multiple organ dysfunction if untreated and accounts for most of the deaths in this disease. The main regulator of body iron content and distribution is hepcidin, inhibiting iron absorption in duodenal enterocytes and release of stored iron from macrophages and hepatocytes. Despite iron overload in patients and mice with β-thalassemia, hepcidin levels are insufficiently increased, as ineffective erythropoiesis dominates hepcidin regulation. Relatively low hepcidin causes iron overload in β-thalassemia. Recent evidence demonstrates that erythroferrone (ERFE), an erythroid regulator of hepcidin, is increased in bone marrow and serum from β-thalassemic patients and th3/+ mice [Kautz Nat Gen 2014] and its loss results in increased hepcidin, partially reversing iron overload in th3/+ mice [Kautz Blood 2015]. In addition, bone marrow ERFE expression normalizes in TfR1 haploinsufficient th3/+ mice [Li Blood 2017]. We hypothesize that the loss of ERFE and TfR1 influences erythropoiesis and iron metabolism in complementary ways in th3/+ mice, and therefore aim to explore iron- and erythropoiesis-related parameters in th3/+ TfR1+/- ERFE-/- (triple mutant (TM)) mice. All models are on a C57BL6 background and have been crossed to generate 4-6 mice for analysis at 6 weeks of age. We confirm our previous reports [Li Blood 2017] that th3/+TfR1+/- mice have increased RBC count and hemoglobin, decreased MCV and reticulocyte count (Table I), and reduce splenomegaly (Fig 1a and 1b) relative to th3/+ mice. We also confirm that th3/+ ERFE-/- mice do not reverse splenomegaly or improve peripheral blood circulating erythroid parameters compared to th3/+ mice [Kautz Blood 2015] (Table I) but exhibit further increase in TfR1 in late stage erythroid precursors (Fig 1c). Analysis of the bone marrow reveals that total erythroid mass is unaltered in triple mutants relative to th3/+, th3/+ ERFE-/-, and th3/+ TfR1+/- mice, but the number of late erythroblasts (poly-E and ortho-E stages) is normalized to WT levels (Fig 1d), strongly suggesting that, unlike in th3/+ erythropoiesis, where the block in differentiation occurs at the poly-E stage, th3/+ TfR1+/- and especially triple mutant mice restore differentiation at this stage to generate a higher hemoglobin. No differences in erythroblast apoptosis or ROS concentration are evident in triple mutant relative to th3/+ ERFE-/- or th3/+ TfR1+/- mice. We also analyzed markers of Epo responsiveness and demonstrate that serum Epo and EpoR expression are increased in th3/+ relative to WT mice (Fig 1e and 1f), but while serum Epo is decreased, EpoR is further increased (Fig 1f). These findings suggest that Epo responsiveness is more optimized in triple mutant erythroblasts, enabling a smaller proportion of late stage erythroblasts to produce circulating RBCs with relatively less serum Epo. Remarkably, while neither th3/+ ERFE-/- and th3/+ TfR1+/- mice reverse iron overload or impact hepcidin expression at 6 weeks of age, triple mutant mice demonstrate fully normalized ratio of hepcidin expression relative to liver iron concentration (LIC) (Fig 1g). Taken together, these experiments provide evidence of the differential and additive effects of TfR1 and ERFE loss in th3/+ mice, with a predominantly erythropoietic benefit of TfR1 loss, a predominantly iron-homeostatic benefit of ERFE loss, and synergy of both in optimizing Epo responsiveness. Disclosures Ganz: Intrinsic LifeScience: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Silarus Pharma: Consultancy, Equity Ownership; Keryx Pharma: Consultancy, Research Funding; Gilead: Consultancy; Ablynx: Consultancy; Vifor: Consultancy; Akebia: Consultancy, Research Funding; La Jolla Pharma: Consultancy, Patents & Royalties: Patent licensed to La Jolla Pharma by UCLA.

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Jasuja, Reema, Anagha Sawant, Debra D. Pittman, and Jie Quan. "Transcriptomic Analysis Reveals Erythroferrone Modulates BMP6 Signaling Pathways Involved in Iron Homeostasis and Metabolism." Blood 132, Supplement 1 (November 29, 2018): 1049. http://dx.doi.org/10.1182/blood-2018-99-118724.

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Abstract Introduction: Erythroferrone (ERFE), the recently identified erythroid regulator of iron absorption, is a member of the C1q/TNF-related protein (CTRP) family. It is produced in erythroblasts in response to an increased erythropoietic drive, downregulates hepcidin expression and thereby promotes intestinal iron absorption and mobilization. The levels of Erfe are inappropriately high under conditions of ineffective erythropoiesis in inherited anemias such as thalassemia and congenital dyserythropoietic anemias. However, the mechanism of Erfe mediated Hepcidin inhibition remains unknown. Here, we use transcriptomic analysis of the human hepatoma cell line, Huh7 to identify genes and pathways involved in hepatocyte response to Erfe. Methods: Huh7 cells were seeded in a 6-well cell culture plate. Twenty four hours later, the cells were washed with PBS, and treated with a recombinant murine ERFE monomeric Fc (mEFRE-FC, 10µg/ml) protein or a control IgG (10 ug/ml) for 1h, 6h or 24h in growth media. RNA was isolated, followed by RNA quantification and quality assessment using a 2100 Agilent Bioanalyzer. ERFE is known to regulate Hepcidin antimicrobial peptide (HAMP) transcription and a treatment effect on HAMP expression was demonstrated by qPCR prior to sequencing. A total of 27 mRNA sequencing libraries were constructed from 1ug of human total RNA with the Illumina TruSeq Stranded mRNA Sample Prep protocol and single-end 75 bp reads were generated on an Illumina NextSeq 500. DESeq2 statistical package was used for differential expression testing. Multiple comparisons were adjusted for using a false discovery rate of 5%. Additionally, results were filtered to consider only those genes that demonstrated a fold-change point estimate >2 in either direction. Pathway analysis was performed using the Biological Process gene sets from the Gene Ontology annotation. Results: Compared to control treated Huh7 cells, 3 transcripts were differentially regulated following a one hour treatment with mERFE-Fc, ID1 (Log2 fold-change -1.55, q-value 4.99E-09), BPIFB2 (Log2 fold-change -1.88, q-value 0.036) and ANO1 (Log2 fold-change -1.43, q-value 0.019). A larger number of genes were differentially regulated with longer treatments, 32 genes at 6h and 828 genes at 24h. Among selected genes differentially expressed at 24h, between control treated and Erfe treated cells, we observed a significant reduction in expression of genes known to be directly upregulated by bone morphogenetic proteins (BMPs), including DNA binding protein inhibitor ID1(ID1), DNA binding protein inhibitor ID2 (ID2), DNA binding protein inhibitor ID3 (ID3) and HAMP. BMP6 has been demonstrated to regulate several biological processes such as iron metabolism in the liver, adipogenesis, and insulin sensitization. Interestingly, we also observed upregulation of SLC27A1 (or FATP1, fatty acid transporter, Log2 fold-change 2.27, q-value 0.003), GDNF (Log2 fold-change 2.57, q-value 2.4E-05), GIPR (Log2 fold-change 2.53, q-value 7.9E-07) upon treatment with Erfe at 24h. Previous work has demonstrated that all of these genes are downregulated by BMP6 treatment 1-3. Pathway analysis indicated a number of genes differentially regulated in the GOBP (gene ontology biological processes) iron ion homeostasis pathway, BMP signaling or TGF-β receptor signaling pathway. This assessment further indicated downregulation of cellular hormone levels and metabolic processes and ion homeostasis as biological processes impacted by erythroferrone. Conclusions: Significant differences in gene expression occur in hepatocytes upon interaction with erythroferrone. Many genes in the iron homeostasis, BMP6 signaling metabolic processes were also differentially regulated. This further supports the mechanism of ERFE on iron homeostasis. Disclosures Jasuja: Pfizer: Employment. Sawant:Pfizer: Employment. Pittman:Pfizer: Employment. Quan:Pfizer: Employment.

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Kautz, Léon, Grace Jung, Elizabeta Nemeth, and Tomas Ganz. "The Erythroid Factor Erythroferrone and Its Role In Iron Homeostasis." Blood 122, no. 21 (November 15, 2013): 4. http://dx.doi.org/10.1182/blood.v122.21.4.4.

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Abstract Introduction In humans and other mammals, erythroid precursors in the bone marrow are the main consumers of iron. The availability of iron for erythropoiesis is controlled by hepcidin-induced endocytosis and degradation of ferroportin, the iron exporter which delivers iron to plasma from absorptive enterocytes and erythrocyte-recycling macrophages. In humans, within less than a day after hemorrhage or the administration of erythropoietin, duodenal iron absorption is increased by a mechanism which presumably evolved to provide for the iron requirement of increased erythropoiesis. Increased iron availability appears to be mediated by the suppression of the hormone hepcidin, thereby increasing ferroportin and delivering more iron to plasma. Increased erythropoietic activity is known to suppress hepcidin, but the molecular mechanism is not understood despite extensive investigation. We report that bleeding or administration of erythropoietin leads to the release of an erythroid factor made by erythroblasts which acts on hepatocytes to suppress hepcidin. Results We examined the mouse hepcidin mRNA response to hemorrhage in wild-type mice or mice lacking hemojuvelin or TfR2, two of the critical mediators of hepcidin synthesis. Wild-type, hemojuvelin and iron-depleted TfR2 mutant mice all responded to hemorrhage by similar suppression of hepcidin mRNA within 9-15h, indicating that hemojuvelin and TfR2 are not essential for this response. We therefore initiated an unbiased search for potential suppressors of hepcidin by examining the time course of bone marrow response to hemorrhage (500 μl) using gene chip-based expression profiling. We identified less than a dozen erythroid-specific transcripts that change prior to the suppression of hepcidin mRNA. Searching for secreted proteins, we focused on a previously unidentified transcript that is highly induced prior to hepcidin suppression, and provisionally named it “erythroferrone” (Erfe). Erfe mRNA expression was greatly increased in the bone marrow and the spleen 4h after phlebotomy or EPO stimulation, preceding hepcidin suppression. Erfe-deficient mice did not suppress hepcidin mRNA after phlebotomy (Figure) or EPO injection and recovered more slowly from phlebotomy-induced anemia than their wild-type counterparts. We did not observe any significant defects in their baseline erythropoiesis or the composition or maturation of erythroid precursors suggesting that Erfe exerts its effect specifically on hepcidin for the regulation of iron availability. Hepcidin expression was reduced by injection of recombinant Erfe (2 μg/g) in wild-type mice. Moreover, treatment of mouse primary hepatocytes with supernatants of HEK293T cells overexpressing Erfe led to a significant decrease in hepcidin expression suggesting that Erfe can act directly on the liver to suppress hepcidin. Importantly, we also found that Erfe mRNA is greatly increased in the marrow and spleen of the mouse model of β-thalassemia Hbbth3/+ compared to wild-type controls. Conclusion Erythroferrone may be the long-sought erythroid factor repressing hepcidin during increased erythropoietic activity, and may contribute to the pathogenesis of iron-loading anemias including β-thalassemia. Disclosures: Nemeth: Intrinsic LifeSciences: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Ganz:Intrinsic LifeSciences: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

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des Georges, Amédée, Yaser Hashem, Anett Unbehaun, Robert A. Grassucci, Derek Taylor, Christopher U. T. Hellen, Tatyana V. Pestova, and Joachim Frank. "Structure of the mammalian ribosomal pre-termination complex associated with eRF1•eRF3•GDPNP." Nucleic Acids Research 42, no. 5 (December 11, 2013): 3409–18. http://dx.doi.org/10.1093/nar/gkt1279.

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Abstract Eukaryotic translation termination results from the complex functional interplay between two release factors, eRF1 and eRF3, in which GTP hydrolysis by eRF3 couples codon recognition with peptidyl-tRNA hydrolysis by eRF1. Here, we present a cryo-electron microscopy structure of pre-termination complexes associated with eRF1•eRF3•GDPNP at 9.7 -Å resolution, which corresponds to the initial pre-GTP hydrolysis stage of factor attachment and stop codon recognition. It reveals the ribosomal positions of eRFs and provides insights into the mechanisms of stop codon recognition and triggering of eRF3’s GTPase activity.

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Horiguchi, Hiroto, Masayoshi Kobune, Kento Ono, Saori Shimoyama, Chisa Fujita, Akari Goto, Hiroshi Ikeda, and Satoshi Iyama. "CD34+ Positive Myelodysplastic Cells with Ring Sideroblasts or SF3B1 Mutation Produce High Erythroferrone and GDF15." Blood 136, Supplement 1 (November 5, 2020): 28–29. http://dx.doi.org/10.1182/blood-2020-134861.

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Background. Iron absorption from gastrointestinal tract was enhanced in a subset of patients with myelodysplastic syndrome (MDS) exhibiting ineffective erythropoiesis. Duodenal iron absorption was achieved via an iron transporter divalent metal transporter (DMT)-1 and ferroportin which was downregulated by hepatic hepcidin. Recently, three erythroid regulators such as growth differentiation factor 15 (GDF15), twisted gastrulation protein homolog 1 (TWSG1) and erythroferrone (ERFE) which down regulated hepatic hepcidin production has been identified. However, it has been not yet clarified which molecules could contribute to the increased iron absorption in patients with MDS. Materials and Methods. In the present study, we examined the expression level of GDF15, TWSG1 and ERFE mRNA during ex vivo erythroid differentiation from sodium butyrate (SB)-treated K562 and CD34+ bone marrow (BM) cells in the presence of 4 U/mL erythropoietin (EPO), 100 U/mL interleukin-3, 10 ng/mL stem cell factor, 20 ng/mL insulin-like growth factor (IGF)-1 and 500 micro g/mL iron-saturated transferrin. We further analyzed the expression level of GDF15 and ERFE by using a GEO dataset (GSE58831). GEO dataset was downloaded as a matrix by GEOquery package (Bioconductor). The numerical data of the matrix were normalized by quantile normalization using limma package. Clinical and sequencing data were downloaded from supplementary materials. Those were combined with a GEO dataset (GSE58831) before analysis. Results. The levels of ERFE and GDF15 mRNA were dramatically increased during erythroid differentiation from SB-treated K562 and normal CD34+ cells in response to EPO in vitro. Using GEO data sets (GSE58831), the levels of ERFE and GDF15 mRNA in CD34+ cells derived from MDS patients were significantly elevated as compared with that from healthy volunteers. Importantly, the levels of ERFE and GDF15 mRNA in CD34+ cells in a subset of MDS with ring sideroblasts (RS) or SF3B1 mutation were significantly and highly elevated as compared with other subsets of MDS (GSE58831). Additionally, the supernatant derived from SB-treated K562 reduced hepcidin level in HepG2 in the presence of EPO. Conclusion. These results suggested that productions of ERFE and GDF15 in CD34+ MDS cells with RS or SF3B1 mutation may be associated with abnormal iron metabolism via hepcidin reduction. These findings may be useful to understanding the high ferritin level in a subset of MDS patients. Figure 1 Disclosures Kobune: Takeda Pharmaceutical Company: Research Funding; Alexion Pharmaceuticals Inc: Research Funding; Novartis Pharma K.K.: Research Funding; ONO PHARMACEUTICAL CO., LTD: Research Funding. Ikeda:Alexion Pharmaceuticals Inc: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Novartis Pharma K.K.: Research Funding; Sanofi K.K.: Research Funding; ONO PHARMACEUTICAL CO., LTD: Research Funding.

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van Vuren, Annelies J., Michele F. Eisenga, Stephanie van Straaten, Andreas Glenthøj, Carlo A. J. M. Gaillard, Stephan J. L. Bakker, Martin H. de Borst, Richard van Wijk, and Eduard J. van Beers. "Interplay of erythropoietin, fibroblast growth factor 23, and erythroferrone in patients with hereditary hemolytic anemia." Blood Advances 4, no. 8 (April 23, 2020): 1678–82. http://dx.doi.org/10.1182/bloodadvances.2020001595.

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Abstract Recently, erythropoietin (EPO) was identified as regulator of fibroblast growth factor 23 (FGF23). Proteolytic cleavage of biologically active intact FGF23 (iFGF23) results in the formation of C-terminal fragments (cFGF23). An increase in cFGF23 relative to iFGF23 suppresses FGF receptor signaling by competitive inhibition. EPO lowers the i:cFGF23 ratio, thereby overcoming iFGF23-mediated suppression of erythropoiesis. We investigated EPO-FGF23 signaling and levels of erythroferrone (ERFE) in 90 patients with hereditary hemolytic anemia (www.trialregister.nl [NL5189]). We show, for the first time, the importance of EPO-FGF23 signaling in hereditary hemolytic anemia: there was a clear correlation between total FGF23 and EPO levels (r = +0.64; 95% confidence interval [CI], 0.09-0.89), which persisted after adjustment for iron load, inflammation, and kidney function. There was no correlation between iFGF23 and EPO. Data are consistent with a low i:cFGF23 ratio. Therefore, as expected, we report a correlation between EPO and ERFE in a diverse set of hereditary hemolytic anemias (r = +0.47; 95% CI, 0.14-0.69). There was no association between ERFE and total FGF23 or iFGF23, which suggests that ERFE does not contribute to the connection between FGF23 and EPO. These findings open a new area of research and might provide potentially new druggable targets with the opportunity to ameliorate ineffective erythropoiesis and the development of disease complications in hereditary hemolytic anemias.

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Dommann, A., H. Vetsch, F. Hulliger, and W. Petter. "Structure of ErFe(CN)6.4H2O." Acta Crystallographica Section C Crystal Structure Communications 46, no. 11 (November 15, 1990): 1992–94. http://dx.doi.org/10.1107/s0108270190002682.

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Russo, Roberta, Immacolata Andolfo, Luigia De Falco, Francesco Manna, Antonella Gambale, Mariasole Bruno, Gianluca De Rosa, Domenico Girelli, Lucia De Franceschi, and Achille Iolascon. "Erfe-Encoding FAM132B in Congenital Dyserythropoietic Anemia Type II." Blood 126, no. 23 (December 3, 2015): 535. http://dx.doi.org/10.1182/blood.v126.23.535.535.

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Abstract Recessive mutations in SEC23B gene cause congenital dyserythropoietic anemia type II (CDAII), a rare hereditary disorder hallmarked by ineffective erythropoiesis, iron overload, and reduced expression of hepatic hormone hepcidin (Iolascon, 2013). The most recently described hepcidin regulator is the erythroblast-derived hormone erythroferrone (ERFE), a member of TNF-α superfamily that specifically inhibits hepcidin production in experimental models (Kautz, 2014). However, the function of ERFE in humans remains to be investigated. To determine whether dysregulation of ERFE expression is associated with ineffective erythropoiesis and iron-loading in CDAII, we studied the ERFE-encoding FAM132B gene expression in 48 SEC23B-related CDAII patients and 29 age and gender matched healthy controls (HCs). Twelve new cases and four novel SEC23B mutations were described. Samples were obtained after informed consent, according to the Declaration of Helsinki. Genomic DNA, mutational screening, RNA isolation, cDNA preparation, and qRT-PCR were performed as previously described (Russo, 2013). All patients were young adults (17.0±2.5 years at diagnosis), with increased serum ferritin (395.4±67.6 ng/mL) and transferrin saturation (71.9±5.4 %). We observed a statistically significant overexpression of FAM132B gene in peripheral blood mononuclear cells from CDAII patients (9.09±0.08) compared to HCs (8.32±0.12, p<0.0001). A similar trend was obtained when evaluating FAM132B expression in reticulocytes from a subset of patients and HCs. Of note, a statistically significant correlation between peripheral blood and reticulocyte FAM132B expression from the same patients was observed (Spearman ρ= 0.78, p=0.02). Although the role of ERFE in peripheral blood is still unknown, our observations suggested that the evaluation of FAM132B mRNA in peripheral blood is a reliable and easy-to-measure marker of ERFE levels. When we divided CDAII patients into two sub-groups accordingly to FAM132B gene expression, we observed a statistically significant reduction in hemoglobin (Hb) level in the high-FAM132B subset (8.6±0.4 g/dL) respect to low-FAM132B one (10.1±0.5 g/dL, p=0.02). Of note, the expression level of FAM132B did not correlate with the transfusion regimen. The higher amount of ERFE reflects the increased iron demand for Hb production as well as the expanding abnormal erythropoiesis, as attested by the increased RDW and sTfR (although not significant) in high-FAM132B patients. This in turn leads to reduced hepcidin in high-FAM132B group (4.2±1.8 nM) compared to low-FAM132B one (5.9±1.8 nM, p=0.05), resulting in augmented iron delivery to the erythron. Although the iron balance data do not differ significantly between the two groups, a tendency to decreased hepcidin/ferritin ratio and increased transferrin saturation was observed in high-FAM132B patients. Thus, FAM132B overexpression seems to contribute to the inappropriate suppression of hepcidin with subsequent hemosiderosis observed in CDAII. Consistent with our previous studies, we observed a reduced SEC23B expression in our patients compared to HC. Indeed, FAM132B and SEC23B gene expression exhibited an inverse correlation (Spearman ρ=-0.36, p=0.01). We confirmed the ex vivo data about inverse correlation between FAM132B and SEC23B expression observed in our patients by establishing K562 SEC23B-silenced cells. To knockdown SEC23B gene expression in K562 cells two different pGIPZ Lentiviral shRNAmir for SEC23B (shSEC23B-70/-74) were used. We observed a higher expression of FAM132B at 5 days of erythroid differentiation in K562 SEC23B-silenced cell compared to not-silenced ones. Conversely, SEC23B expression was lower in both shSEC23B compared to sh-CTR at 2 and 5 days of differentiation. Although the mechanisms of hemin-induced differentiation are quite different from EPO-induced ones, we can hypothesize that FAM132B over-expression is related to the maturative arrest and the subsequent increased number of erythroid precursors. This study provides the first analysis on ERFE regulation in humans. Our data suggest that ERFE over-expression in CDAII patients is the result of both physiological and pathological mechanisms leading to hepcidin suppression in condition of dyserythropoiesis. Nevertheless, it seems that ERFE cannot be the main erythroid regulator of hepcidin suppression, at least in CDAII patients. Disclosures No relevant conflicts of interest to declare.

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Ganz, Tomas, Grace Jung, Arash Naeim, Yelena Ginzburg, Zahra Pakbaz, Patrick B. Walter, Léon Kautz, and Elizabeta Nemeth. "Immunoassay for human serum erythroferrone." Blood 130, no. 10 (September 7, 2017): 1243–46. http://dx.doi.org/10.1182/blood-2017-04-777987.

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Delaye, Jean-Baptiste, Hugo Alarcan, Nicolas Vallet, Charlotte Veyrat-Durebex, Louis Bernard, Olivier Hérault, Martine Ropert, et al. "Specific changes of erythroid regulators and hepcidin in patients infected by SARS-COV-2." Journal of Investigative Medicine 70, no. 4 (March 15, 2022): 934–38. http://dx.doi.org/10.1136/jim-2021-002270.

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Iron metabolism is tightly linked to infectious and inflammatory signals through hepcidin synthesis. To date, iron homeostasis during SARS-CoV-2 infection has not yet been described. The aim of this study is to characterize the hepcidin and erythroid regulators (growth differentiation factor 15 (GDF-15) and erythroferrone (ERFE)) by measuring concentrations in plasma in context of COVID-19 disease.We performed a single-center observational study of patients with COVID-19 to evaluate concentrations of main regulatory proteins involved in iron homeostasis, namely: hepcidin, ERFE and GDF-15. SARS-CoV-2 infection (COVID-19+) was defined by a positive RT-PCR. Sixteen patients with COVID-19+ were gender-matched and age-matched to 16 patients with a sepsis unrelated to SARS-CoV-2 (COVID-19−) and were compared with non-parametric statistic test.Clinical and hematological parameters, plasma iron, transferrin, transferrin saturation, ferritin, soluble transferrin receptor and C reactive protein were not statistically different between both groups. Median plasma hepcidin concentrations were higher in the COVID-19+ group (44.1 (IQR 16.55–70.48) vs 14.2 (IQR 5.95–18.98) nmol/L, p=0.003), while median ERFE and GDF-15 concentrations were lower in the COVID-19+ group (0.16 (IQR 0.01–0.73) vs 0.89 (IQR 0.19–3.82) ng/mL, p=0.035; 2003 (IQR 1355–2447) vs 4713 (IQR 2082–7774) pg/mL, p=0015), respectively) compared with the COVID-19− group.This is the first study reporting lower ERFE and GDF-15 median concentrations in patients with COVID-19+ compared with patients with COVID-19−, associated with an increased median concentration of hepcidin in the COVID-19+ group compared with COVID19− group.

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Thompson, Alexis A., Tomas Ganz, Mary Therese Forsyth, Elizabeta Nemeth, and Sherif M. Badawy. "Does Gene Therapy in Beta Thalassemia Normalize Novel Markers of Ineffective Erythropoiesis and Iron Homeostasis?" Blood 134, Supplement_1 (November 13, 2019): 816. http://dx.doi.org/10.1182/blood-2019-129658.

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BACKGROUND: Ineffective erythropoiesis in thalassemia alters iron homeostasis, predisposing to systemic iron overload. Successful allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia major corrects anemia, should eliminate ineffective erythropoiesis (IE) and normalize iron homeostasis (IH). Whether gene therapy (GT) will fully correct IE and IH is not known. This cross-sectional observational study evaluated the iron status of patients with beta thalassemia following HSCT or GT, and compared them with cohorts of patients with thalassemia intermedia (TI) or transfusion-dependent thalassemia (TDT) using recently introduced biomarkers along with imaging studies and other clinical assessments to better understand and characterize IE and IH across groups. METHODS: We evaluated a convenience sample of 29 participants with beta thalassemia (median age 25 years, IQR 21-35; females 55%; Asian 52%). Participants in the HSCT (n=6) and GT (n=10) groups were evaluated on average 116.5 and 46.9 months following cell infusion, respectively. TDT patients (n= 9) were evaluated pre-transfusion and off iron chelation for at least 7 days, and TI (n=4) were un-transfused or not transfused in >3 years. Clinical lab assessments and MRI R2*/ T2* to assess heart and liver iron burden including post-processing, were performed using local clinical protocols. ELISAs for hepcidin, erythroferrone (Erfe) and GDF-15 were performed in a blinded manner. RESULTS: Median values for all IE and IH parameters tested were normal in the HSCT group, and were significantly lower than in all other groups. There were significant differences among all groups for hemoglobin (p=0.003), erythropoietin (Epo) (p=0.03), serum ferritin (SF) (p=0.01), transferrin (p=0.006), soluble transferrin receptor (sTfR) (p=0.02), serum hepcidin: serum ferritin (H:F) ratio (p=0.006), Erfe (p=0.001), GDF15 (p=0.003), and liver iron content (LIC) by MRI R2* (p=0.02). H:F ratio, a surrogate for predisposition to systemic iron loading, inversely correlated with Erfe (rs= -0.85, p<0.0001), GDF15 (rs= -0.69, p=0.0001) and liver R2* (rs= -0.66, p=0.0004). In a multivariate analysis, adjusted for gender and race, H:F ratio and Epo levels predicted Erfe and GDF15 (p=0.05 and p=0.06; p=0.01 and p=0.05), respectively. Even after excluding GT patients that are not transfusion independent (N=2), SF, Epo, sTfR and hepcidin remain abnormal in the GT group, and there were no significant differences in these parameters between GT and TDT. However, novel biomarkers of IH and IE suggested lower ineffective erythropoiesis in GT compared to TDT (median (IQR) Erfe, 12 (11.6-25.2) vs. 39.6 (24.5-54.7), p=0.03; GDF15, 1909.9 (1389-4431) vs. 8906 (4421-12331), p=0.02), respectively. Erfe and GDF15 were also lower in GT compared to TI, however these differences did not reach statistical significance. There were no differences in hepcidin, ferritin, or H:F by race, however Erfe and GDF15 were significantly lower in Asians compared to non-Asians (p=0.006 and p=0.02, respectively). CONCLUSION: Nearly 4 years post infusion, most subjects with TDT treated with GT are transfusion independent with near normal hemoglobin, however, studies in this limited cohort using conventional measures suggest IE and IH improve, particularly when transfusion support is no longer needed, however they remain abnormal compared to HSCT recipients, who using these parameters appear to be cured. STfR did not detect differences, however GDF15 and Erfe were more sensitive assays that could demonstrate significant improvement in IE and IH with GT compared to TDT. Contribution to IE by uncorrected stem cell populations post GT cannot be determined. Transduction enhancement and other recent improvements to GT may yield different results. Longitudinal studies are needed to determine if thalassemia patients treated with GT will have ongoing IE predisposing to systemic iron overload. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership. Nemeth:Intrinsic LifeSciences: Consultancy, Equity Ownership; Silarus Therapeutics: Consultancy, Equity Ownership; Keryx: Consultancy; Ionis Pharmaceuticals: Consultancy; La Jolla Pharma: Consultancy; Protagonist: Consultancy.

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45

Mullica, D. F., H. O. Perkins, E. L. Sappenfield, and D. Leschnitzer. "Structure of monoclinic ErFe(CN)6.4H2O." Acta Crystallographica Section C Crystal Structure Communications 45, no. 2 (February 1, 1989): 330–31. http://dx.doi.org/10.1107/s0108270188011667.

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46

Marsh, R. E. "Structure of ErFe(CN)6.4H2O. Corrigendum." Acta Crystallographica Section C Crystal Structure Communications 45, no. 8 (August 15, 1989): 1270. http://dx.doi.org/10.1107/s0108270189004300.

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47

Xiang-dong, Sun, Yan Qi-wei, Zhang Pan-lin, Hu Bo-ping, Wang Kai-ying, and Wang Yi-zhong. "Neutron-powder-diffraction study of ErFe 11.35 Nb 0.65 and ErFe 11.35 Nb 0.65 N y." Acta Physica Sinica (Overseas Edition) 4, no. 12 (December 1995): 912–16. http://dx.doi.org/10.1088/1004-423x/4/12/005.

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48

Berezovsky, Betty, Martin Báječný, Jana Frýdlová, Iuliia Gurieva, Daniel Wayne Rogalsky, Petr Přikryl, Vít Pospíšil, Emanuel Nečas, Martin Vokurka, and Jan Krijt. "Effect of Erythropoietin on the Expression of Murine Transferrin Receptor 2." International Journal of Molecular Sciences 22, no. 15 (July 30, 2021): 8209. http://dx.doi.org/10.3390/ijms22158209.

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Erythropoietin (EPO) downregulates hepcidin expression to increase the availability of iron; the downregulation of hepcidin is mediated by erythroferrone (ERFE) secreted by erythroblasts. Erythroblasts also express transferrin receptor 2 (TFR2); however, the possible role of TFR2 in hepcidin downregulation is unclear. The purpose of the study was to correlate liver expression of hepcidin with the expression of ERFE and TFR2 in murine bone marrow and spleen at 4, 16, 24, 48, 72 and 96 h following administration of a single dose of EPO. Splenic Fam132b expression increased 4 h after EPO injection; liver hepcidin mRNA was decreased at 16 h. In the spleen, expression of TFR2 and transferrin receptor (TFR1) proteins increased by an order of magnitude at 48 and 72 h after EPO treatment. The EPO-induced increase in splenic TFR2 and TFR1 was associated with an increase in the number of Tfr2- and Tfr1-expressing erythroblasts. Plasma exosomes prepared from EPO-treated mice displayed increased amount of TFR1 protein; however, no exosomal TFR2 was detected. Overall, the results confirm the importance of ERFE in stress erythropoiesis, support the role of TFR2 in erythroid cell development, and highlight possible differences in the removal of TFR2 and TFR1 from erythroid cell membranes.

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49

Li, Yihang, Gregory R. Booth, Qi Feng, and Robert E. Fleming. "Hypoferremia of Fasting in Mice Is Associated with Increased Hepcidin and Decreased Erythroferrone Expression." Blood 124, no. 21 (December 6, 2014): 4026. http://dx.doi.org/10.1182/blood.v124.21.4026.4026.

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Abstract Background: Protein-calorie restriction in humans is associated with changes in iron metabolism that differ from dietary iron-deficiency. Dietary iron absorption and tissue iron distribution and are regulated by the hepatocellular peptide hormone hepcidin, which mediates a decrease in circulating iron concentrations and increase in cellular iron stores. Hepcidin is upregulated in response to increased serum and tissue iron, upregulated in response to ER-stress via the transcription factor CREB-H, and down-regulated in response to erythroid iron demand via the circulating signaling molecule erythroferrone/myonectin (ERFE). An overnight fast was reported to decrease expression of skeletal muscle ERFE in mice. Objective: The aim of this study was to investigate the regulation of hepcidin in the hypoferremia of fasting. Design/Methods: We analyzed parameters of iron homeostasis in five 5 week old male AKR mice fasted for 18 hours overnight (and allowed access to water) compared with mice with access to chow ad libitum. Serum and tissue iron concentrations were measured. Liver hepcidin mRNA was quantified by real-time RT-PCR and verified by Northern blot analysis. Marrow ERFE and liver CREB-H mRNA expression was quantified by RT-PCR and normalized to beta actin. Results: As anticipated, fasted mice had significantly lower serum iron concentrations (203 vs 321 mcg/dL, P<0.001) and transferrin saturations (64.4 vs 79.6%, P<0.05). Duodenal iron concentrations were increased in fasted mice, 2.3-fold (P<0.01). Histochemical staining demonstrated iron retention in the absorptive enterocytes. Liver (916 vs 735 mcg/g, P=0.1) and splenic (480 vs 414 mcg/g, P=0.001) iron concentrations were modestly higher in the fasted mice. Despite hypoferremia, the fasted mice demonstrated increased liver hepcidin expression (1.9 fold, P < 0.05). Liver CREB-H mRNA expression was increased ~10 fold, P<0.01; however there was no change in liver XBP-1 processing (marker of ER stress). Marrow ERFE expression was downregulated by approximately one third (P<0.01). Conclusions: The fasting state in mice is associated with increased hepcidin expression, iron retention in absorptive enterocytes, and decreased circulating iron. These observations suggest that the hypoferremia of fasting is not consequent to limited iron availability, but rather to hepcidin-mediated retention of iron in the duodenum and storage tissues. They moreover support a role for nutritional state, independent of iron status, as a regulator of hepcidin and mediated by changes in expression of ERFE and CREB-H. Disclosures No relevant conflicts of interest to declare.

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Nai, Antonella, Aude Rubio, Alessandro Campanella, Ophélie Gourbeyre, Irene Artuso, Jessica Bordini, Aurélie Gineste, et al. "Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice." Blood 127, no. 19 (May 12, 2016): 2327–36. http://dx.doi.org/10.1182/blood-2015-11-681494.

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Key Points Hyperactivation of the BMP-SMAD pathway blunts EPO-mediated hepcidin inhibition. Lack of BMP-SMAD pathway inhibition by matriptase-2 abrogates the ERFE-mediated hepcidin suppression in response to EPO.

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