title: Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia.
abstract: Erythroid hypoplasia (EH) is a rare complication associated with recombinant human erythropoietin (rHuEPO) therapies, due to development of anti-rHuEPO antibodies; however, the underlying mechanisms remain poorly clarified. Our aim was to manage a rat model of antibody-mediated EH induced by rHuEPO and study the impact on iron metabolism and erythropoiesis. Wistar rats treated during 9 weeks with a high rHuEPO dose (200 IU) developed EH, as shown by anemia, reduced erythroblasts, reticulocytopenia, and plasmatic anti-rHuEPO antibodies. Serum iron was increased and associated with mRNA overexpression of hepatic hepcidin and other iron regulatory mediators and downregulation of matriptase-2; overexpression of divalent metal transporter 1 and ferroportin was observed in duodenum and liver. Decreased EPO expression was observed in kidney and liver, while EPO receptor was overexpressed in liver. Endogenous EPO levels were normal, suggesting that anti-rHuEPO antibodies blunted EPO function. Our results suggest that anti-rHuEPO antibodies inhibit erythropoiesis causing anemia. This leads to a serum iron increase, which seems to stimulate hepcidin expression despite no evidence of inflammation, thus suggesting iron as the key modulator of hepcidin synthesis. These findings might contribute to improving new therapeutic strategies against rHuEPO resistance and/or development of antibody-mediated EH in patients under rHuEPO therapy.
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, . 3000-548 Coimbra, Portugal ; Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal.
authors.forename: J C
authors.initials: JC
authors.lastname: Fernandes
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, . 3000-548 Coimbra, Portugal.
authors.forename: P
authors.initials: P
authors.lastname: Garrido
authors.affiliation: Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal ; Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Ribeiro
authors.affiliation: Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal ; Research Centre in Health Sciences, University of Beira Interior, 6201-001 Covilhã, Portugal.
authors.forename: P
authors.initials: P
authors.lastname: Rocha-Pereira
authors.affiliation: Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal ; Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal.
authors.forename: E
authors.initials: E
authors.lastname: Bronze-da-Rocha
authors.affiliation: Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal ; Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal.
authors.forename: L
authors.initials: L
authors.lastname: Belo
authors.affiliation: Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal ; Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal.
authors.forename: E
authors.initials: E
authors.lastname: Costa
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, . 3000-548 Coimbra, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Reis
authors.affiliation: Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal ; Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Santos-Silva
mesh_terms: D000741:Anemia, Aplastic / Q000097:blood* / Q000139:chemically induced / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000009:adverse effects; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D064451:Hepcidins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007501:Iron / Q000097:blood*; D008565:Membrane Proteins / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D012697:Serine Endopeptidases / Q000096:biosynthesis
chemical_list: D000906:Antibodies; D064451:Hepcidins; D008565:Membrane Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin; D007501:Iron; D012697:Serine Endopeptidases; C467801:matriptase 2