An activin receptor IIA ligand trap corrects ineffective erythropoiesis in ß-thalassemia.
Nat Med
; 20(4): 398-407, 2014 Apr.
Article
em En
| MEDLINE
| ID: mdl-24658077
ABSTRACT
The pathophysiology of ineffective erythropoiesis in ß-thalassemia is poorly understood. We report that RAP-011, an activin receptor IIA (ActRIIA) ligand trap, improved ineffective erythropoiesis, corrected anemia and limited iron overload in a mouse model of ß-thalassemia intermedia. Expression of growth differentiation factor 11 (GDF11), an ActRIIA ligand, was increased in splenic erythroblasts from thalassemic mice and in erythroblasts and sera from subjects with ß-thalassemia. Inactivation of GDF11 decreased oxidative stress and the amount of α-globin membrane precipitates, resulting in increased terminal erythroid differentiation. Abnormal GDF11 expression was dependent on reactive oxygen species, suggesting the existence of an autocrine amplification loop in ß-thalassemia. GDF11 inactivation also corrected the abnormal ratio of immature/mature erythroblasts by inducing apoptosis of immature erythroblasts through the Fas-Fas ligand pathway. Taken together, these observations suggest that ActRIIA ligand traps may have therapeutic relevance in ß-thalassemia by suppressing the deleterious effects of GDF11, a cytokine which blocks terminal erythroid maturation through an autocrine amplification loop involving oxidative stress and α-globin precipitation.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Recombinantes de Fusão
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Eritroblastos
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Talassemia beta
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Proteínas Morfogenéticas Ósseas
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Receptores de Activinas Tipo II
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Eritropoese
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Fatores de Diferenciação de Crescimento
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Hematínicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Nat Med
Assunto da revista:
BIOLOGIA MOLECULAR
/
MEDICINA
Ano de publicação:
2014
Tipo de documento:
Article