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Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia.

抗红铁蛋白N端结构域的抗体防止铁调素抑制并改善小鼠地中海贫血。

  • 影响因子:7.27
  • DOI:10.1182/blood.2019003140
  • 作者列表:"Arezes J","Foy N","McHugh K","Quinkert D","Benard S","Sawant A","Frost JN","Armitage AE","Pasricha SR","Lim PJ","Tam MS","Lavallie E","Pittman DD","Cunningham O","Lambert M","Murphy JE","Draper SJ","Jasuja R","Drakesmith H
  • 发表时间:2020-02-20
Abstract

:Erythroferrone (ERFE) is produced by erythroblasts in response to erythropoietin (EPO) and acts in the liver to prevent hepcidin stimulation by BMP6. Hepcidin suppression allows for the mobilization of iron to the bone marrow for the production of red blood cells. Aberrantly high circulating ERFE in conditions of stress erythropoiesis, such as in patients with β-thalassemia, promotes the tissue iron accumulation that substantially contributes to morbidity in these patients. Here we developed antibodies against ERFE to prevent hepcidin suppression and to correct the iron loading phenotype in a mouse model of β-thalassemia [Hbb(th3/+) mice] and used these antibodies as tools to further characterize ERFE's mechanism of action. We show that ERFE binds to BMP6 with nanomolar affinity and binds BMP2 and BMP4 with somewhat weaker affinities. We found that BMP6 binds the N-terminal domain of ERFE, and a polypeptide derived from the N terminus of ERFE was sufficient to cause hepcidin suppression in Huh7 hepatoma cells and in wild-type mice. Anti-ERFE antibodies targeting the N-terminal domain prevented hepcidin suppression in ERFE-treated Huh7 cells and in EPO-treated mice. Finally, we observed a decrease in splenomegaly and serum and liver iron in anti-ERFE-treated Hbb(th3/+) mice, accompanied by an increase in red blood cells and hemoglobin and a decrease in reticulocyte counts. In summary, we show that ERFE binds BMP6 directly and with high affinity, and that antibodies targeting the N-terminal domain of ERFE that prevent ERFE-BMP6 interactions constitute a potential therapeutic tool for iron loading anemias.

摘要

: 红铁蛋白 (ERFE) 由成红细胞响应促红细胞生成素 (EPO) 而产生,并在肝脏中发挥作用以防止bmp6对铁调素的刺激。铁调素抑制允许铁向骨髓动员以产生红细胞。在应激红细胞生成的条件下,例如在 β-地中海贫血患者中,异常高的循环ERFE促进组织铁积累,这基本上有助于这些患者的发病。在这里,我们开发了针对ERFE的抗体,以防止铁调素抑制和纠正 β-地中海贫血 [Hbb(th3/+) 小鼠] 小鼠模型中的铁负载表型,并将这些抗体用作进一步表征ERFE作用机制的工具。我们显示ERFE以纳摩尔亲和力结合BMP6,并以稍弱的亲和力结合BMP2和BMP4。我们发现BMP6结合ERFE的N端结构域,ERFE的N端衍生的多肽足以在Huh7肝癌细胞和野生型小鼠中引起铁调素抑制。靶向N末端结构域的抗ERFE抗体在ERFE处理的Huh7细胞和EPO处理的小鼠中阻止铁调素抑制。最后,我们在抗ERFE处理的Hbb(th3/+) 小鼠中观察到脾肿大以及血清和肝铁的减少,伴随着红细胞和血红蛋白的增加以及网织红细胞计数的减少。总之,我们表明ERFE直接以高亲和力结合BMP6,并且靶向ERFE N端结构域的抗体可以防止ERFE-BMP6相互作用,这是铁负载贫血的潜在治疗工具。

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影响因子:1.74
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DOI:10.1177/1049909119868657
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血红蛋白病方向

由于血红蛋白分子结构异常(异常血红蛋白病),或珠蛋白肽链合成速率异常(珠蛋白生成障碍性贫血,又称海洋性贫血)所引起的一组遗传性血液病。

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