RESUMO
Under normal conditions, iron metabolism is carefully regulated to sustain normal cellular functions and the production of hemoglobin in erythroid cells. Perturbation to the erythropoiesis-iron metabolism axis can result in iron imbalances and cause anemia or organ toxicity. Various congenital and acquired diseases associated with abnormal red cell production are characterized by aberrant iron absorption. Several recent studies have shown that improvements in red blood cell production also ameliorate iron metabolism and vice versa. Many therapeutics are now under development with the potential to improve a variety of hematologic diseases, from ß-thalassemia and iron-refractory iron deficiency anemia to anemia of inflammation and polycythemia vera. This review summarizes selected mechanisms related to red cell production and iron metabolism and describes potential therapeutics and their current uses. We also consider the potential application of the discussed therapeutics on various diseases, alone or in combination. The vast repertoire of drugs under development offers new opportunities to improve the clinical care of patients suffering from congenital or acquired red blood cell disorders with limited or no treatment options.
Assuntos
Anemia Ferropriva , Doenças Hematológicas , Talassemia beta , Humanos , Eritropoese , Eritrócitos/metabolismo , Ferro/metabolismo , Talassemia beta/metabolismo , Doenças Hematológicas/tratamento farmacológicoRESUMO
ß-Thalassemia intermedia is a disorder characterized by ineffective erythropoiesis (IE), anemia, splenomegaly, and systemic iron overload. Novel approaches are being explored based on the modulation of pathways that reduce iron absorption (ie, using hepcidin activators like Tmprss6-antisense oligonucleotides [ASOs]) or increase erythropoiesis (by erythropoietin [EPO] administration or modulating the ability of transferrin receptor 2 [Tfr2] to control red blood cell [RBC] synthesis). Targeting Tmprss6 messenger RNA by Tmprss6-ASO was proven to be effective in improving IE and splenomegaly by inducing iron restriction. However, we postulated that combinatorial strategies might be superior to single therapies. Here, we combined Tmprss6-ASO with EPO administration or removal of a single Tfr2 allele in the bone marrow of animals affected by ß-thalassemia intermedia (Hbbth3/+). EPO administration alone or removal of a single Tfr2 allele increased hemoglobin levels and RBCs. However, EPO or Tfr2 single-allele deletion alone, respectively, exacerbated or did not improve splenomegaly in ß-thalassemic mice. To overcome this issue, we postulated that some level of iron restriction (by targeting Tmprss6) would improve splenomegaly while preserving the beneficial effects on RBC production mediated by EPO or Tfr2 deletion. While administration of Tmprss6-ASO alone improved the anemia, the combination of Tmprss6-ASO + EPO or Tmprss6-ASO + Tfr2 single-allele deletion produced significantly higher hemoglobin levels and reduced splenomegaly. In conclusion, our results clearly indicate that these combinatorial approaches are superior to single treatments in ameliorating IE and anemia in ß-thalassemia and could provide guidance to translate some of these approaches into viable therapies.
Assuntos
Eritropoetina/administração & dosagem , Eritropoetina/genética , Terapia Genética/métodos , Proteínas de Membrana/antagonistas & inibidores , Oligonucleotídeos Antissenso/administração & dosagem , Talassemia beta/terapia , Animais , Células Cultivadas , Eritropoese/efeitos dos fármacos , Eritropoese/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Ferro/metabolismo , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/prevenção & controle , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oligonucleotídeos Antissenso/farmacologia , Receptores da Transferrina/genética , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Talassemia beta/metabolismoAssuntos
Proteínas Morfogenéticas Ósseas/deficiência , Fatores de Diferenciação de Crescimento/deficiência , Proteínas Recombinantes de Fusão/farmacologia , Talassemia beta/metabolismo , Anemia/sangue , Anemia/tratamento farmacológico , Anemia/etiologia , Animais , Biomarcadores , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Modelos Animais de Doenças , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/metabolismo , Camundongos , Camundongos Transgênicos , Resultado do Tratamento , Talassemia beta/sangue , Talassemia beta/tratamento farmacológico , Talassemia beta/genéticaRESUMO
ß-Thalassemia (BT) is an inherited genetic disorder that is characterized by ineffective erythropoiesis (IE), leading to anemia and abnormal iron metabolism. IE is an abnormal expansion of the number of erythroid progenitor cells with unproductive synthesis of enucleated erythrocytes, leading to anemia and hypoxia. Anemic patients affected by BT suffer from iron overload, even in the absence of chronic blood transfusion, suggesting the presence of ≥1 erythroid factor with the ability to modulate iron metabolism and dietary iron absorption. Recent studies suggest that decreased erythroid cell differentiation and survival also contribute to IE, aggravating the anemia in BT. Furthermore, hypoxia can also affect and increase iron absorption. Understanding the relationship between iron metabolism and IE could provide important insights into the BT condition and help to develop novel treatments. In fact, genetic or pharmacological manipulations of iron metabolism or erythroid cell differentiation and survival have been shown to improve IE, iron overload, and anemia in animal models of BT. Based on those findings, new therapeutic approaches and drugs have been proposed; clinical trials are underway that have the potential to improve erythrocyte production, as well as to reduce the iron overload and organ toxicity in BT and in other disorders characterized by IE.
Assuntos
Eritropoese , Distúrbios do Metabolismo do Ferro/etiologia , Distúrbios do Metabolismo do Ferro/patologia , Ferro/metabolismo , Talassemia beta/complicações , Animais , Humanos , Talassemia beta/patologiaAssuntos
Eritropoese/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Piridonas/farmacologia , Talassemia beta/tratamento farmacológico , Animais , Deferiprona , Modelos Animais de Doenças , Eritropoese/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Talassemia beta/genética , Talassemia beta/metabolismoRESUMO
The thalassemia syndromes (α- and ß-thalassemia) are the most common and frequent disorders associated with ineffective erythropoiesis. Imbalance of α- or ß-globin chain production results in impaired red blood cell synthesis, anemia, and more erythroid progenitors in the blood stream. While patients affected by these disorders show definitive altered parameters related to erythropoiesis, the relationship between the degree of anemia, altered erythropoiesis, and dysfunctional iron metabolism has not been investigated in both α-thalassemia carriers (ATC) and ß-thalassemia carriers (BTC). Here, we demonstrate that ATC have a significantly reduced hepcidin and increased soluble transferrin receptor levels but relatively normal hematological findings. In contrast, BTC have several hematological parameters significantly different from controls, including increased soluble transferrin receptor and erythropoietin levels. These changes in both groups suggest an altered balance between erythropoiesis and iron metabolism. The index sTfR/log ferritin and (hepcidin/ferritin)/sTfR are, respectively, increased and reduced relative to controls, proportional to the severity of each thalassemia group. In conclusion, we showed in this study, for the first time in the literature, that thalassemia carriers have altered iron metabolism and erythropoiesis.