title: Inhibitory effects of simvastatin on migration and invasion of rheumatoid fibroblast-like synoviocytes by preventing geranylgeranylation of RhoA.
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.
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Xiao
authors.forename: Liuqin
authors.initials: L
authors.lastname: Liang
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Pan
authors.forename: Fan
authors.initials: F
authors.lastname: Lian
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.forename: Haobo
authors.initials: H
authors.lastname: Lin
authors.forename: Di
authors.initials: D
authors.lastname: Fu
authors.forename: Jinjin
authors.initials: J
authors.lastname: Fan
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Hanshi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000737:chemistry / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D054876:Prenylation / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D020742:rhoA GTP-Binding Protein