Osteopontin small interfering RNA protects mice from fulminant hepatitis
Osteopontin small interfering RNA protects mice from fulminant hepatitis
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DOI：
10.1089/hum.2007.069
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发表时间：
2007-12-01
影响因子：
4.2
通讯作者：
Uede, Toshimitsu
中科院分区：
文献类型：
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作者：
Saito, Yoshinari;Kon, Shigeyuki;Uede, Toshimitsu
骨桥蛋白(OPN)与多种辅助性T细胞1型免疫介导性疾病有关，包括类风湿性关节炎(RA)、多发性硬化症(MS)、克罗恩病和重型肝炎。骨桥蛋白在这些疾病的病变灶中表达增强。在小鼠体内注射中和抗OPN抗体已成功地治疗RA和重型肝炎。抗体治疗可能会引起副作用，包括对异种抗体蛋白的过敏反应，从而需要抗体人源化。为了提供中和OPN功能的替代方法，本研究探索了使用OPN小干扰RNA(SiRNA)沉默OPN基因表达的可能性。在体外，OPN siRNA有效地沉默了外源性和内源性OPN基因的表达。静脉注射OPN siRNA后，OPN siRNA被有效地输送到肝脏，从而有效地沉默了OPN基因在肝脏中的表达。在刀豆蛋白A(ConA)诱导的小鼠重型肝炎模型中，OPN在肝脏中的表达增加，并导致严重的肝脏坏死。重要的是，经OPN siRNA治疗后，OPN在肝脏中的表达水平显著降低，肝组织损伤得到改善，表现为血清丙氨酸转氨酶水平显著降低，肝脏组织学基本正常。因此，本研究表明，OPN siRNA对各种炎症性疾病具有治疗潜力，而OPN在体内通过沉默OPN基因的表达而发挥关键作用。
Osteopontin (OPN) has been implicated in various helper T cell type 1 immunity-mediated diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), Crohn's disease, and fulminant hepatitis. Increased expression of OPN has been detected in pathological foci of these diseases. RA and fulminant hepatitis have been successfully treated by administration of neutralizing anti-OPN antibody in mice. Antibody treatment may elicit side effects including allergic reactions against heterologous antibody proteins, thus necessitating humanization of antibody. To provide alternative means to neutralize OPN function, in this study we explored the possibility of using OPN small interfering RNA (siRNA) to silence OPN gene expression. In vitro, OPN siRNA efficiently silenced the expression of both exogenous and endogenous OPN gene. After hydrodynamic intravenous injection of OPN siRNA, OPN siRNA was efficiently delivered to the liver, which resulted in the efficient silencing of OPN gene expression in liver. In a murine model of concanavalin A (ConA)-induced fulminant hepatitis, OPN expression was elevated in liver and severe hepatic necrosis was induced. Importantly, after OPN siRNA treatment, the OPN expression level in liver was significantly reduced and liver tissue injury was ameliorated, as reflected by the significant reduction of serum alanine aminotransferase levels and almost normal liver histology. Thus, this study indicates that OPN siRNA delivery has therapeutic potential in various inflammatory diseases in which OPN play a critical role by silencing OPN gene expression in vivo.