Pathobiology of hemophilic synovitis I:: overexpression of mdm2 oncogene
Pathobiology of hemophilic synovitis I:: overexpression of mdm2 oncogene
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DOI：
10.1182/blood-2003-12-4231
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发表时间：
2004-10-01
期刊：
影响因子：
20.3
通讯作者：
Valentino, LA
中科院分区：
文献类型：
--
作者：
Hakobyan, N;Kazarian, T;Valentino, LA
血友病是一种遗传性疾病，由凝血因子VIII或IX缺乏引起。关节出血是血友病最常见的表现。血关节病导致一种称为血友病滑膜炎(HS)的炎性和增殖性疾病。随着时间的推移，一种衰弱的、致残性的关节炎--血友病关节病--发展起来。虽然从关节出血到滑膜炎再到关节病的临床顺序已经被很好地记录下来，但血液中的一个或多个成分以及导致血友病滑膜炎的分子变化尚不清楚。长期以来，人们一直怀疑铁是罪魁祸首，但一直缺乏直接证据。此前，我们发现铁促进了人类滑膜细胞的增殖并诱导了c-myc的表达。在这里，我们展示了体内出血和体外铁导致P53结合蛋白MDM2表达增加。铁诱导正常人滑膜细胞MDM2的表达约为8倍。在人类血友病A的小鼠模型中，血关节病导致了人类血友病滑膜炎的病理变化和滑膜细胞增殖的显著增加。在体外，铁诱导MDM2的表达。铁在血液中引起的分子变化可能是细胞增殖增加和血友病滑膜炎发生的基础。(C)2004年，由美国血液病学会提供。
Hemophilia is a genetic disease caused by a deficiency of blood coagulation factor VIII or IX. Bleeding into joints is the most frequent manifestation of hemophilia. Hemarthrosis results in an inflammatory and proliferative disorder termed hemophilic synovitis (HS). In time, a debilitating, crippling arthritis, hemophilic arthropathy, develops. Although the clinical sequence of events from joint bleeding to synovitis to arthropathy is well documented, the component or components in blood and the molecular changes responsible for hemophilic synovitis are not known. Iron has long been suspected to be the culprit but direct evidence has been lacking. Previously, we showed that iron increased human synovial cell proliferation and induced c-myc expression. Here we show that bleeding into a joint in vivo and iron in vitro result in increased expression of the p53-binding protein, mdm2. Iron induced the expression of mdm2 by normal human synovial cells approximately 8-fold. In a murine model of human hemophilia A, hemarthrosis resulted in pathologic changes observed in human hemophilic synovitis and a marked increase in synovial cell proliferation. Iron, in vitro, induced the expression of mdm2. The molecular changes induced by iron in the blood may be the basis of the increase in cell proliferation and the development of hemophilic synovitis. (C) 2004 by The American Society of Hematology.