A Comprehensive Analysis of the Erythropoietin-erythroferrone-hepcidin Pathway in Hereditary Hemolytic Anemias

Vuren, Annelies J. Van; Sharfo, Alaa; Grootendorst, Simon T; Straaten, Stephanie van; Punt, Arjen; Petersen, Jesper; Fassi, Daniel El; Solinge, Wouter W. van; Bartels, Marije; Wijk, Richard van; Glenthøj, Andreas; Beers, Eduard J. van

doi:10.1097/hs9.0000000000000627

Cited by 12 publications

(15 citation statements)

References 15 publications

(35 reference statements)

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“…Interestingly, they showed decreased hepcidin values, although to a lesser extent to those observed in CDAII cases, corroborating the observation that ERFE is not the only erythroid regulator that contribute to hepcidin inhibition [24]. Our results agree with a recent study investigating the EPO-ERFE-hepcidin pathway in PKD, HS, and beta-thalassemia patients [25].…”

Section: Discussionsupporting

confidence: 92%

Evaluation of the Main Regulators of Systemic Iron Homeostasis in Pyruvate Kinase Deficiency

Zaninoni

Marra

Fermo

et al. 2022

Preprint

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Iron homeostasis and dyserythropoiesis are poorly investigated in pyruvate kinase deficiency (PKD), the most common glycolytic defect of erythrocytes. Herein, we studied the main regulators of iron balance and erythropoiesis, as soluble transferrin receptor (sTfR), hepcidin, erythroferrone (ERFE), and erythropoietin (EPO), in a cohort of 41 PKD patients, compared with 42 affected by congenital hemolytic anemia type II (CDAII) and 50 with hereditary spherocytosis (HS). PKD patients showed intermediate values of hepcidin and ERFE between CDAII and HS, and clear negative correlations between log-transformed hepcidin and log-EPO (Person’s r correlation coefficient = -0.34), log-hepcidin and log-ERFE (r = -0.47), and log-hepcidin and sTfR (r = -0.44). sTfR was significantly higher in PKD; EPO levels were similar in PKD and CDAII, both higher than in HS. Finally, genotype-phenotype correlation in PKD showed that more severe patients, carrying non-missense/non-missense genotypes, had lower hepcidin and increased ERFE, EPO, and sTFR compared with the others (missense/missense and missense/non-missense), suggesting a higher rate of ineffective erythropoiesis. We herein investigated the main regulators of systemic iron homeostasis in the largest cohort of PKD patients described so far, opening new perspectives on the molecular basis and therapeutic approaches of this disease.

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Section: Discussionsupporting

confidence: 92%

Evaluation of the Main Regulators of Systemic Iron Homeostasis in Pyruvate Kinase Deficiency

Zaninoni

Marra

Fermo

et al. 2022

Preprint

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“…Differences in standards between mouse and human assays and potential differences in the relative potency of mouse and human erythroferrone preclude direct comparison of ERFE concentrations between mouse models and humans. Nevertheless, the broad range of serum ERFE concentrations in our transgenic mice likely encompasses the broad range of ERFE levels reported in humans, including those with hemolytic anemias with ineffective erythropoiesis 12,20 . In our mouse models, the large changes in ERFE protein concentrations that result from much smaller changes in Erfe mRNA expression suggest decreasing clearance of plasma ERFE at high concentrations.…”

Section: Discussionmentioning

confidence: 95%

“…While patients with β-thalassemia commonly suffer from problems that could be linked to disruptions in BMP signaling, including iron overload 13 , renal impairment 14 , and skeletal problems such as impaired growth 15 or bone mineralization 16 , it is unclear to which extent the observed pathologies are attributable to elevated ERFE as opposed to other factors such as tissue and organ hypoxia, the effects of hemolytic products or the toxicity of treatment. Animal models of increased ERFE production depend on the stimuli of anemia 17,18 or EPO administration 19 but serum ERFE levels in these models could be orders of magnitude lower than in human patients with β-thalassemia 12,20 . Additionally, high EPO levels exert multiple systemic effects 21 beyond increasing Erfe expression and these complicate direct attribution of observed phenotypes to the action of ERFE alone .…”

Section: Introductionmentioning

confidence: 99%

Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice

Coffey¹,

Jung²,

Olivera³

et al. 2022

Blood

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The hormone erythroferrone (ERFE) is produced by erythroid cells in response to hemorrhage, hypoxia or other erythropoietic stimuli, and suppresses the hepatic production of the iron-regulatory hormone hepcidin, thereby mobilizing iron for erythropoiesis. Suppression of hepcidin by ERFE is thought to be mediated by interference with paracrine 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 three lines of transgenic mice with graded erythroid overexpression of ERFE and showed 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 where 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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Section: Discussionmentioning

confidence: 61%

“…In a recent study we successfully used the assay for patients with various forms of hereditary haemolytic anaemias, to characterize the interplay between erythropoiesis and iron levels. 26 The calculated upper reference limit is 11.2 nmol/ L. The lower reference limit, based on this data set is below the quality control samples used in this study. Although some differences were reported in hepcidin reference intervals in a previous study between male and female and with age and time of the day, the dataset in this study is too limited to further differentiate reference intervals between sex and age.…”

Section: Discussionmentioning

confidence: 61%

An easy, fast, and efficient assay for the quantification of peptide Hepcidin-25 in serum and plasma with LC-MS/MS.

et al. 2022

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The peptide hormone hepcidin-25 plays an important role in iron metabolism. Low or high levels of hepcidin-25 are associated with various iron disorders, therefore hepcidin-25 is an important biomarker. This study describes an easy and fast analytical assay for the quantification of hepcidin-25 with liquid chromatography-tandem mass spectrometry (LC–MS/MS). Sample preparation was performed by protein precipitation with trichloroacetic acid, and injection onto a LC-MS/MS was directly conducted from a LoBind 96-well plate. The concentration range covered by the quality control samples, ranged from 0.25 nmol/L (12.3% CV) to 11.9 nmol/L (CV < 9%). Matrix effect was limited (mean recovery of 99.9% with a CV of 6.4%). The assay was validated for serum, EDTA and heparin plasma. An international secondary reference material was used for calibration. The reference interval (90% CL) was estimated for hepcidin-25 by analyzing serum and plasma samples from 156 healthy subjects with a lower limit: 0.12 (0.07-0.19) and upper limit: 11.2 nmol/L (9.5-13.0). Finally, the assay was successfully used for the detection of various forms of hereditary hemolytic anemias, to characterize the interplay between erythropoiesis and iron levels.

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A Comprehensive Analysis of the Erythropoietin-erythroferrone-hepcidin Pathway in Hereditary Hemolytic Anemias

Cited by 12 publications

References 15 publications

Evaluation of the Main Regulators of Systemic Iron Homeostasis in Pyruvate Kinase Deficiency

Evaluation of the Main Regulators of Systemic Iron Homeostasis in Pyruvate Kinase Deficiency

Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice

An easy, fast, and efficient assay for the quantification of peptide Hepcidin-25 in serum and plasma with LC-MS/MS.

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