Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin
Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin
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DOI：
10.1182/blood-2006-09-048868
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发表时间：
2007-06-01
期刊：
影响因子：
20.3
通讯作者：
Rivella, Stefano
中科院分区：
文献类型：
--
作者：
Gardenghi, Sara;Marongiu, Maria F.;Rivella, Stefano
进行性铁超载是β-地中海贫血最显著、最终也是致命的并发症。然而，关于无效红细胞生成(IE)、铁调节基因的作用和组织铁分布在β-地中海贫血中的关系，人们知之甚少。我们分析了1岁以下小鼠的组织铁含量和铁调节基因在肝脏、十二指肠、脾、骨髓、肾脏和心脏中的表达，这些小鼠表现出与中间型β-地中海贫血(th3/+)和重型(th3/th3)一致的铁超载和贫血水平。在这里，我们第一次显示，在Th3/+和Th3lth3小鼠中，组织和细胞铁的分布是异常的和不同的，输血疗法可以拯救受严重β-地中海贫血影响的小鼠，并改变铁的吸收和分布。我们的研究表明，IE的程度决定了组织铁的分布，IE和铁含量调控着海普西丁(Hamp1)和其他铁调节基因，如We和CEBPA。在年轻的th3/+和th3/th3小鼠中，低水平的Hamp1导致铁吸收增加。然而，在1岁的Th3/+动物中，Hamp1的水平上升，相反，正是端口铁蛋白(Fpn1)的增加维持了铁的积累，从而揭示了这种铁转运体在β-地中海贫血铁超载中的基础作用。
Progressive iron overload is the most salient and ultimately fatal complication of beta-thalassemia. However, little is known about the relationship among ineffective erythropoiesis (IE), the role of iron-regulatory genes, and tissue iron distribution in beta-thalassemia. We analyzed tissue iron content and iron-regulatory gene expression in the liver, duodenum, spleen, bone marrow, kidney, and heart of mice up to 1 year old that exhibit levels of iron overload and anemia consistent with both beta-thalassemia intermedia (th3/+) and major (th3/th3). Here we show, for the first time, that tissue and cellular iron distribution are abnormal and different in th3/+ and th3lth3 mice, and that transfusion therapy can rescue mice affected by beta-thalassemia major and modify both the absorption and distribution of iron. Our study reveals that the degree of IE dictates tissue iron distribution and that IE and iron content regulate hepcidin (Hamp1) and other iron-regulatory genes such as We and Cebpa. In young th3/+ and th3/th3 mice, low Hamp1 levels are responsible for increased iron absorption. However, in 1-year-old th3/+ animals, Hamp1 levels rise and it is rather the increase of ferroportin (Fpn1) that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the iron overload of beta-thalassemia.