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Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):384-390
Iron Metabolism & its Disorders
Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure
Paul Robach,1* Elena Gammella,2* Stefania Recalcati,2 Domenico Girelli,3 Annalisa Castagna,3 Matthieu Roustit,4 Carsten Lundby,5 Anne-Kristine Lundby,5 Pierre Bouzat,4 Samuel Vergès,6 Guillaume Séchaud,4 Pierluigi Banco,4 Mario Uhr,7 Catherine Cornu,8 Pierre Sallet9 and Gaetano Cairo2
1National School for Mountain Sports, Chamonix, France; 2Department of Biomedical Sciences for Health, University of Milan, Italy; 3Department of Medicine, University of Verona, Italy; 4Grenoble Alpes University Hospital, Grenoble, France; 5Center for Physical Activity Research, University Hospital, Copenhagen, Denmark; 6HP2 Laboratory, U1042, Grenoble Alpes University, INSERM, Grenoble, France; 7Department of Hematology Synlab-Suisse, Lugano, Switzerland; 8Hospices Civils de Lyon INSERM CIC1407/UMR5558, Hôpital Louis Pradel, Bron, France and 9“Athletes for Transparency” Association, Lyon, France
*PR and EG contributed equally as co-first authors.
ABSTRACT
The erythropoietin (Epo)-erythroferrone (ERFE)-hepcidin axis coor- dinates erythropoiesis and iron homeostasis. While mouse studies have established that Epo-induced ERFE production represses hep- cidin 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 stud- ies. First, 24 males were given six injections of saline (placebo), recombi- nant Epo (rhEpo) at a dose of 20 IU/kg (micro-dose) or rhEpo at 50 IU/kg (low dose). Second, we quantified ERFE in 22 subjects exposed to high altitude (3800 m) for 15 h. In the first study, total hemoglobin mass (Hbmass) increased after low- but not after micro-dose injections, when compared to the mass after placebo injections. Serum ERFE levels were enhanced by rhEpo, remaining higher than after placebo for 48 h (micro-dose) or 72 h (low-dose) after injections. Conversely, hepcidin levels decreased when Epo and ERFE rose, before any changes in serum iron parameters occurred. In the second study, serum Epo and ERFE increased at high alti- tude. The present results demonstrate that in healthy humans ERFE responds to slightly increased Epo levels not associated with Hbmass expan- sion and downregulates hepcidin in an apparently iron-independent way. Notably, ERFE flags micro-dose Epo, thus holding promise as a novel bio- marker of doping.
Introduction
Erythropoiesis and iron metabolism are tightly linked and an inadequate iron supply to developing erythrocytes results in anemia, a condition affecting a large segment of the world’s population. The coordination between erythropoietic activ- ity and iron homeostasis is provided by hepcidin, which controls body iron balance by negatively regulating the activity of the iron exporter, ferroportin.1,2 Hepcidin expression is inhibited by iron deficiency and high erythropoietic activity,1,2 a response that increases iron availability to meet iron needs for hemoglobin synthe- sis. Accordingly, we and others have demonstrated that recombinant human ery- thropoietin (rhEpo) administration to healthy humans is followed by a prompt downregulation of hepcidin.3-5 The identification and characterization of erythro- ferrone (ERFE), a hepcidin-inhibiting factor produced by erythroblasts in response to Epo, provided an additional link between erythropoietic activity and iron home- ostasis.6 Mouse studies established that ERFE synthesized in response to Epo impairs hepcidin transcription by inhibiting hepatic BMP/SMAD signaling.6,7 The
Correspondence:
GAETANO CAIRO
gaetano.cairo@unimi.it
PAUL ROBACH
paul.robach@ensm.sports.gouv.fr
Received: July 31, 2019. Accepted: January 2, 2020. Pre-published: January 9, 2020.
https://doi.org/10.3324/haematol.2019.233874
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