BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice.
BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice.
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DOI：
10.1053/j.gastro.2010.07.044
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发表时间：
2010-11
期刊：
影响因子：
29.4
通讯作者：
Babitt JL
中科院分区：
文献类型：
--
作者：
Corradini E;Schmidt PJ;Meynard D;Garuti C;Montosi G;Chen S;Vukicevic S;Pietrangelo A;Lin HY;Babitt JL
肝素调节异常是HFE血色病发病机制的核心。肝骨形态发生蛋白6(BMP6)-SMAD信号转导通路是控制海普西丁表达的主要调控机制，最近发现该通路在hFE基因敲除(hFE−/−)小鼠中受损。为了更明确地确定HFE是否通过与Bmp6-SMAD信号通路的相互作用来调节Hepsidin的表达，我们研究了肝脏HFE过表达是否激活Bmp6-SMAD途径来诱导Hepsidin的表达。然后，我们研究了过量的外源性Bmp6给药是否克服了Bmp6-smad信号的损伤，并改善了HFE−/−小鼠的血色病。以野生型(WT)小鼠为对照，研究了Bmp6-SMAD通路及Bmp6抗体的中和作用。用外源性Bmp6处理HFE、−/−和WT小鼠，分析其蛋白表达和铁参数的变化。HFE-TG小鼠表现为肝素过量和缺铁性贫血。与WT小鼠相比，HFE TG小鼠肝脏Bmp6-SMAD靶基因表达增加，而HFE TG小鼠注射抗Bmp6抗体可改善HFE TG小鼠的肝杀蛋白过量和铁缺乏。在HFE−/−小鼠中，超生理剂量的外源性Bmp6改善了海普西丁缺乏，降低了血清铁，并将组织铁重新分配到适当的存储位置。HFE与Bmp6-SMAD信号通路相互作用，调节Hepsidin的表达，但HFe不是Bmp6诱导Hepsidin所必需的。小鼠的外源性Bmp6治疗弥补了HFE血色素沉着症的分子缺陷，Bmp6样激动剂可能作为这种疾病的替代治疗策略。
Abnormal hepcidin regulation is central to the pathogenesis of HFE hemochromatosis. Hepatic bone morphogenetic protein 6 (BMP6)-SMAD signaling is a main regulatory mechanism controlling hepcidin expression, and this pathway was recently demonstrated to be impaired in Hfe knockout (Hfe−/−) mice. To more definitively determine whether HFE regulates hepcidin expression through an interaction with the BMP6-SMAD signaling pathway, we investigated whether hepatic Hfe overexpression activates the BMP6-SMAD pathway to induce hepcidin expression. We then investigated whether excess exogenous BMP6 administration overcomes the BMP6-SMAD signaling impairment and ameliorates hemochromatosis in Hfe−/− mice. The BMP6-SMAD pathway and the effects of neutralizing BMP6 antibody were examined in Hfe transgenic mice (Hfe Tg) compared with wildtype (WT) mice. Hfe−/− and WT mice were treated with exogenous BMP6 and analyzed for hepcidin expression and iron parameters. Hfe Tg mice exhibited hepcidin excess and iron deficiency anemia. Hfe Tg mice also exhibited increased hepatic BMP6-SMAD target gene expression compared with WT mice, while anti-BMP6 antibody administration to Hfe Tg mice improved the hepcidin excess and iron deficiency. In Hfe−/− mice, supraphysiologic doses of exogenous BMP6 improved hepcidin deficiency, reduced serum iron, and redistributed tissue iron to appropriate storage sites. HFE interacts with the BMP6-SMAD signaling pathway to regulate hepcidin expression, but HFE is not necessary for hepcidin induction by BMP6. Exogenous BMP6 treatment in mice compensates for the molecular defect underlying Hfe hemochromatosis, and BMP6-like agonists may have a role as an alternative therapeutic strategy for this disease.
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DOI：
10.1053/j.ajkd.2009.12.030
发表时间：
2010-04
期刊：
American journal of kidney diseases : the official journal of the National Kidney Foundation
影响因子：
--
作者：
Babitt JL;Lin HY
通讯作者：
Lin HY
影响因子：
168.9
作者：
Bridle, KR;Frazer, DM;Ramm, GA
通讯作者：
Ramm, GA
影响因子：
15.9
作者：
Babitt, Jodie L.;Huang, Franklin W.;Lin, Herbert Y.
通讯作者：
Lin, Herbert Y.
影响因子：
4.8
作者：
Goswami, Tapasree;Andrews, Nancy C.
通讯作者：
Andrews, Nancy C.
DOI：
10.1073/pnas.96.23.13312
发表时间：
1999-11-09
影响因子：
11.1
作者：
Bahram, S;Gilfillan, S;Schümann, K
通讯作者：
Schümann, K