Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice
Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice
复制标题
DOI：
10.1172/jci66969
复制
发表时间：
2013-04-01
影响因子：
15.9
通讯作者：
Rivella, Stefano
中科院分区：
文献类型：
--
作者：
Guo, Shuling;Casu, Carla;Rivella, Stefano
β-地中海贫血和HFE相关血色素沉着症是世界上最常见的遗传性疾病。这两种疾病的特点是铁调素（HAMP），调节铁吸收的激素水平低。因此，受这些疾病影响的患者表现出铁过载，这是发病率和死亡率的主要原因。HAMP表达受SMAD 1，5，8/SMAD 4复合物的激活控制。TMPRSS 6是一种丝氨酸蛋白酶，可降低SMAD活化并阻断HAMP表达。我们鉴定了靶向小鼠Tmprss 6的第二代反义寡核苷酸（ASO）。阿索治疗血色素沉着症（Hfe（-/-））小鼠显著降低血清铁，转铁蛋白饱和度和肝脏铁积累。此外，受β-地中海贫血影响的小鼠（HBBth 3/+小鼠，下文称为th 3/+小鼠）的阿索治疗减少了不溶性膜结合球蛋白、ROS和细胞凋亡的形成，并改善了贫血。这些动物还表现出较低的红细胞生成素水平，无效红细胞生成（IE）和脾肿大显着改善，以及总血红蛋白水平增加。这些数据表明，靶向Tmprss 6的ASO可能对血色素沉着症、β-地中海贫血和相关疾病的个体有益。
beta-Thalassemia and HFE-related hemochromatosis are 2 of the most frequently inherited disorders worldwide. Both disorders are characterized by low levels of hepcidin (HAMP), the hormone that regulates iron absorption. As a consequence, patients affected by these disorders exhibit iron overload, which is the main cause of morbidity and mortality. HAMP expression is controlled by activation of the SMAD1,5,8/SMAD4 complex. TMPRSS6 is a serine protease that reduces SMAD activation and blocks HAMP expression. We identified second generation antisense oligonucleotides (ASOs) targeting mouse Tmprss6. ASO treatment in mice affected by hemochromatosis (Hfe(-/-)) significantly decreased serum iron, transferrin saturation and liver iron accumulation. Furthermore, ASO treatment of mice affected by beta-thalassemia (HBBth3/+ mice, referred to hereafter as th3/+ mice) decreased the formation of insoluble membrane-bound globins, ROS, and apoptosis, and improved anemia. These animals also exhibited lower erythropoietin levels, a significant amelioration of ineffective erythropoiesis (IE) and splenomegaly, and an increase in total hemoglobin levels. These data suggest that ASOs targeting Tmprss6 could be beneficial in individuals with hemochromatosis, beta-thalassemia, and related disorders.