PI3 kinase/Akt/HIF-1α pathway is associated with hypoxia-induced epithelial-mesenchymal transition in fibroblast-like synoviocytes of rheumatoid arthritis (Retracted Article)
PI3 kinase/Akt/HIF-1α pathway is associated with hypoxia-induced epithelial-mesenchymal transition in fibroblast-like synoviocytes of rheumatoid arthritis (Retracted Article)
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DOI：
10.1007/s11010-012-1463-z
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发表时间：
2013-01-01
影响因子：
4.3
通讯作者：
Liu, Yan-Qing
中科院分区：
文献类型：
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作者：
Li, Guo-Qing;Zhang, Yu;Liu, Yan-Qing
成纤维细胞样滑膜细胞（FLS）的迁移和侵袭在类风湿关节炎（RA）的发病机制中至关重要。RA关节中存在低氧条件，并且低氧在血管生成和炎症中已被广泛研究。然而，其对RA-FLS迁移和侵袭的影响尚不清楚。在这项研究中，我们观察到暴露于缺氧条件下的RA-FLS经历了上皮-间充质转化（EMT），细胞迁移和侵袭增加。我们证明了低氧诱导的EMT伴随着低氧诱导因子（HIF）-1 α表达的增加和Akt的激活。在低氧条件下，用小干扰RNA（siRNA）或金雀异黄素（Gen）敲低或抑制HIF-1 α后，FLS的EMT转化和侵袭能力得以恢复。HIF-1 α可被磷脂酰肌醇3-激酶（PI 3 K）抑制剂LY 294002阻断，表明HIF-1 α的激活受PI 3 K/Akt通路的调节。在胶原诱导的关节炎大鼠模型中，从初次免疫后第20天开始，每周两次给予LY 294002（20 mg/kg，腹膜内）和每天给予Gen（25 mg/kg，通过管饲法），持续3周，显著减轻了关节的临床体征、放射学进展、滑膜增生和炎性细胞浸润。因此，本研究的结果表明，PI 3 K/Akt/HIF-1 α通路的激活在介导缺氧诱导的EMT转化和缺氧条件下RA-FLS的侵袭中起着关键作用。
Migration and invasion of fibroblast-like synoviocytes (FLSs) are critical in the pathogenesis of rheumatoid arthritis (RA). Hypoxic conditions are present in RA joints, and hypoxia has been extensively studied in angiogenesis and inflammation. However, its effect on the migration and invasion of RA-FLSs remains unknown. In this study, we observed that RA-FLSs exposed to hypoxic conditions experienced epithelial-mesenchymal transition (EMT), with increased cell migration and invasion. We demonstrated that hypoxia-induced EMT was accompanied by increased hypoxia-inducible factor (HIF)-1 alpha expression and activation of Akt. After knockdown or inhibition of HIF-1 alpha in hypoxia by small interfering RNA or genistein (Gen) treatment, the EMT transformation and invasion ability of FLSs were regained. HIF-1 alpha could be blocked by phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, indicating that HIF-1 alpha activation was regulated by the PI3K/Akt pathway. Administration of LY294002 (20 mg/kg, intra-peritoneally) twice weekly and Gen (25 mg/kg, by gavage) daily for 3 weeks from day 20 after primary immunization in a collagen-induced arthritis rat model, markedly alleviated the clinical signs, radiology progression, synovial hyperplasia, and inflammatory cells infiltration of joints. Thus, results of this study suggest that activation of the PI3K/Akt/HIF-1 alpha pathway plays a pivotal role in mediating hypoxia-induced EMT transformation and invasion of RA-FLSs under hypoxia.