Inhibitory effects of simvastatin on migration and invasion of rheumatoid fibroblast-like synoviocytes by preventing geranylgeranylation of RhoA
Inhibitory effects of simvastatin on migration and invasion of rheumatoid fibroblast-like synoviocytes by preventing geranylgeranylation of RhoA
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辛伐他汀通过阻止RhoA香叶基香叶基化对类风湿成纤维样滑膜细胞迁移和侵袭的抑制作用
DOI：
10.1007/s00296-012-2383-7
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发表时间：
2013-02
影响因子：
4
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Xiao Y;Liang L;Pan Y;Li L;Li H;Fan J;Yang X;Sun L;Xu H
为探讨辛伐他汀对类风湿关节炎（RA）患者成纤维样滑膜细胞（FLS）迁移和侵袭的影响及其细胞信号转导机制，用3%FBS或GM-CSF刺激活动期RA患者FLS，观察辛伐他汀对FLS迁移和侵袭的影响。Boyden小室法检测细胞的体外迁移和侵袭能力。通过apull-downassay评估RhoA活性。采用酶谱法检测基质金属蛋白酶-2（MMP-2）活性。辛伐他汀通过RA FLS以剂量依赖性方式抑制FBS或GM-CSF诱导的迁移，并且这种抑制作用不依赖于细胞凋亡。我们还发现，辛伐他汀抑制体外侵袭，粘附，MMP-2活性，细胞骨架重组和RhoA激活。此外，甲羟戊酸或GGPP治疗逆转辛伐他汀的抑制作用，不仅在体外迁移和侵袭，而且对RhoA的激活，并通过特异性siRNA转染抑制RhoA减少RA FLS的迁移，粘附和侵袭。这项研究表明，辛伐他汀通过阻止蛋白质香叶基香叶基化和RhoA活化来减少RA FLS的迁移和侵袭。这些发现为他汀类药物可能对预防RA关节炎的破坏提供了新的证据，也表明RhoA可能是调节RA FLS迁移和侵袭的新靶点。
To investigate the effect of simvastatin on the migration and invasion of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and its cellular signal mechanisms, FLS from active RA patients were stimulated with 3 % FBS or GM-CSF in the presence or absence of simvastatin. Cells migration and invasion in vitro were measured by the Boyden chamber method. RhoA activity was assessed by apull-downassay. Matrix metalloproteinases-2 (MMP-2) activity was evaluated by zymography. Simvastatin inhibits FBS- or GM-CSF-induced migration in a dose-dependent manner by RA FLS, and this inhibitory effect is independent of cell apoptosis. We also found that simvastatin suppressed in vitro invasion, adhesion, MMP-2 activity, cytoskeletal reorganization and RhoA activation. Furthermore, mevalonate or GGPP treatment reversed the inhibitory effect of simvastatin not only on migration and invasion in vitro but also on RhoA activation, and inhibition of RhoA by specific siRNA transfection reduced migration, adhesion and invasion of RA FLS. This study shows that simvastatin reduces RA FLS migration and invasion through the prevention of protein geranylgeranylation and RhoA activation. These findings provide a novel evidence that statin may be benefit for preventing RA arthritic destruction, and also indicate that RhoA may be a new target for the modulation of RA FLS migration and invasion.
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影响因子：
4.9
作者：
Skapenko A;Leipe J;Lipsky PE;Schulze-Koops H
通讯作者：
Schulze-Koops H
影响因子：
--
作者：
Anne Roivainen;J. Jalava;Laura Pirilä;T. Yli-Jama;Hannu Tiusanen;Paavo Toivanen
通讯作者：
Anne Roivainen;J. Jalava;Laura Pirilä;T. Yli-Jama;Hannu Tiusanen;Paavo Toivanen
DOI：
--
发表时间：
1997
期刊：
--
影响因子：
--
作者：
G. Firestein
通讯作者：
G. Firestein
影响因子：
--
作者：
Nagashima, T;Okazaki, H;Minota, S
通讯作者：
Minota, S
DOI：
--
发表时间：
2005-11
期刊：
The Journal of rheumatology
影响因子：
--
作者：
Canan Tıkız;O. Utuk;T. Pırıldar;O. Bayturan;P. Bayındır;F. Taneli;H. Tıkız;C. Tuzun
通讯作者：
Canan Tıkız;O. Utuk;T. Pırıldar;O. Bayturan;P. Bayındır;F. Taneli;H. Tıkız;C. Tuzun