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Inhibitory effects of simvastatin on migration and invasion of rheumatoid fibroblast-like synoviocytes by preventing geranylgeranylation of RhoA

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Abstract

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 a pull-down assay. 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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Acknowledgments

The authors would like to thank Yanlong Yang and Xiuqing Dong for their technical assistance. This work is supported by grants from National Natural Science Foundation of China (grant number u0772001 and 81072484), Ministry of Education Foundation, China (grant number 20100171110058), Guangdong Natural Science Foundation (grant number 2011020002358) and Guangdong Project of Science and Technology (grant number 2011B080701011, 2008B080703015).

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No conflict of interest has been declared by authors.

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Authors and Affiliations

  1. Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, People’s Republic of China

    Youjun Xiao, Liuqin Liang, Fan Lian, Haobo Lin, Di Fu, Xiuyan Yang & Hanshi Xu

  2. Department of Rheumatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Yunfeng Pan

  3. Division of Rheumatology and Nephrology, The Affiliated Hospital, Guiyang Medical College, Guiyang, China

    Long Li

  4. Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Jinjin Fan

  5. Department of Pathology, School of Medicine, Northwestern University, Chicago, IL, USA

    Lin Sun

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  1. Youjun Xiao
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Correspondence to Hanshi Xu.

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Youjun Xiao, Liuqin Liang and Yunfeng Pan contributed equally to this work.

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Xiao, Y., Liang, L., Pan, Y. et al. Inhibitory effects of simvastatin on migration and invasion of rheumatoid fibroblast-like synoviocytes by preventing geranylgeranylation of RhoA. Rheumatol Int 33, 389–399 (2013). https://doi.org/10.1007/s00296-012-2383-7

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  • DOI: https://doi.org/10.1007/s00296-012-2383-7

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