Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure
Open Access
- 9 January 2020
- journal article
- research article
- Published by Ferrata Storti Foundation (Haematologica) in Haematologica
- Vol. 106 (2), 384-390
- https://doi.org/10.3324/haematol.2019.233874
Abstract
The erythropoietin (Epo)-erythroferrone (ERFE)-hepcidin axis coordinates erythropoiesis and iron homeostasis. While mouse studies have established that Epo-induced ERFE production represses hepcidin synthesis by inhibiting hepatic BMP/SMAD signaling, evidence for the role of ERFE in humans is limited. To investigate the role of ERFE as a physiological erythroid regulator in humans, we conducted two studies: first, 24 males received six injections of saline (placebo), recombinant Epo (rhEpo) 20 UI kg-1 (micro-dose) or 50 UI kg-1 (low-dose). Second, we quantified ERFE in 22 subjects exposed to high altitude (3800 m) for 15 hours. In the first study, total hemoglobin mass (Hbmass) increased after low- but not after micro-dose injections, when compared to placebo. Serum ERFE levels were enhanced by rhEpo, remaining higher than after placebo for 48 (micro-dose) or 72 hours (low-dose) post-injections. Conversely, hepcidin levels decreased when Epo and ERFE arose, before any changes in serum iron parameters occurred. In the second study, serum Epo and ERFE increased at high altitude. The present results demonstrate that in healthy humans ERFE responds to slightly increased Epo levels not associated with Hbmass expansion and down-regulates hepcidin in an apparently iron-independent way. Notably, ERFE flags micro-dose Epo, thus holding promise as novel anti-doping biomarker.Keywords
This publication has 25 references indexed in Scilit:
- Hepcidin as a potential biomarker for blood dopingDrug Testing and Analysis, 2016
- Associations among Erythroferrone and Biomarkers of Erythropoiesis and Iron Metabolism, and Treatment with Long-Term Erythropoiesis-Stimulating Agents in Patients on HemodialysisPLOS ONE, 2016
- Identification of erythroferrone as an erythroid regulator of iron metabolismNature Genetics, 2014
- Serum hepcidin levels and muscle iron proteins in humans injected with low‐ or high‐dose erythropoietinEuropean Journal of Haematology, 2013
- Regulation of hepcidin expression at high altitudeBlood, 2012
- Blood doping and its detectionBlood, 2011
- Current markers of the Athlete Blood Passport do not flag microdose EPO dopingEuropean Journal of Applied Physiology, 2011
- Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidinHaematologica, 2009
- Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietinBlood, 2009
- A global strategy for prevention and detection of blood doping with erythropoietin and related drugs.2000