Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia
Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia
复制标题
DOI：
10.1182/blood-2012-01-401885
复制
发表时间：
2012-05-24
期刊：
影响因子：
20.3
通讯作者：
Camaschella, Clara
中科院分区：
文献类型：
--
作者：
Nai, Antonella;Pagani, Alessia;Camaschella, Clara
关键铁调节因子hepcidin （HAMP）的不适当低表达导致未输血的β -地中海贫血中间体患者铁超载，HAMP调节可改善Hbb（th3/+）小鼠的地中海贫血表型。HAMP的表达是由铁通过骨形态发生蛋白（BMP）激活的，BMP是母亲抗十足瘫痪的信号通路，并通过一种未知的“红细胞调节剂”被无效的红细胞生成所抑制。丝氨酸蛋白酶TMPRSS6切割BMP共受体血幼蛋白，使BMP通路失活。在这里，我们发现Hbb（th3/+）小鼠中Tmprss6的纯合缺失改善了贫血，减少了无效的红细胞生成、脾肿大和铁负荷。所有这些作用都是通过抑制铁的吸收和再循环的Hamp上调介导的。由于缺乏Tmprss6的Hbb（th3/+）小鼠表现出残留的无效红细胞生成，我们的研究结果表明Tmprss6对于红细胞调节因子抑制Hamp至关重要。我们还在Tmprss6单倍体不足的Hbb（th3/+）雄性而非雌性小鼠中获得了部分表型校正，并表明所观察到的性别差异反映了铁和红细胞生成介导的Hamp调节之间的不平衡。我们的研究表明，预防铁超载可以改善β -地中海贫血，并加强Tmprss6在Hamp抑制中的重要作用，这证明了Tmprss6操作可以为这种疾病提供一种新的治疗选择。(血。2012;119 (21):5021 - 5029)
Inappropriately low expression of the key iron regulator hepcidin (HAMP) causes iron overload in untransfused patients affected by beta-thalassemia intermedia and Hamp modulation provides improvement of the thalassemic phenotype of the Hbb(th3/+) mouse. HAMP expression is activated by iron through the bone morphogenetic protein (BMP)-son of mothers against decapentaplegic signaling pathway and inhibited by ineffective erythropoiesis through an unknown "erythroid regulator." The BMP pathway is inactivated by the serine protease TMPRSS6 that cleaves the BMP coreceptor hemojuvelin. Here, we show that homozygous loss of Tmprss6 in Hbb(th3/+) mice improves anemia and reduces ineffective erythropoiesis, splenomegaly, and iron loading. All these effects are mediated by Hamp up-regulation, which inhibits iron absorption and recycling. Because Hbb(th3/+) mice lacking Tmprss6 show residual ineffective erythropoiesis, our results indicate that Tmprss6 is essential for Hamp inhibition by the erythroid regulator. We also obtained partial correction of the phenotype in Tmprss6 haploinsufficient Hbb(th3/+) male but not female mice and showed that the observed sex difference reflects an unequal balance between iron and erythropoiesis-mediated Hamp regulation. Our study indicates that preventing iron overload improves beta-thalassemia and strengthens the essential role of Tmprss6 for Hamp suppression, providing a proof of concept that Tmprss6 manipulation can offer a novel therapeutic option in this condition. (Blood. 2012;119(21):5021-5029)