Simvastatin Induces Apoptosis of Fibroblast-Like Synoviocytes~!2009-02-16~!2009-03-24~!2009-09-07~!

Litinsky, Ira; Golan, Itshak; Yaron, Michael; Yaron, I; Caspi, Dan; Elkayam, Ori

doi:10.2174/1874312900903010035

Cited by 7 publications

(2 citation statements)

References 34 publications

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“…The 2200-fold upregulation of BNIP3 , a pro-apoptotic protein, in RA FLS led us to investigate apoptosis as a mechanism of observed cell cytotoxicity in TLR2 activated FLS. SMV as a single treatment has previously been shown to cause apoptosis in NHS [32]. Annexin V flow cytometry assay indeed showed a dose dependent apoptosis with SMV (Figure 4 A-D).…”

Section: Resultsmentioning

confidence: 57%

Immunomodulatory effects of Simvastatin in Toll-like receptor-2 stimulated Rheumatoid arthritis synoviocytes

Saeed

Al-Karakooly

Ali

et al. 2022

Preprint

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Fibroblast-like synoviocytes (FLS) are major effector cells in Rheumatoid arthritis (RA). Toll-like receptor-2 (TLR2) activation of FLS plays a key role in RA pathogenesis. Recently, statins have been shown to modulate RA. We investigated the immunomodulatory effects of simvastatin (SMV) in vitro, in FLS cell lines from control and RA subjects, in the presence of TLR2 activation. Normal and RA FLS cultures (1x10^5 cells/well) were treated with SMV then activated with TLR2 ligand (Pam3CSK4 100ug/ml) for 24-hours. SMV caused dose-dependent cytotoxicity in both cell lines as assessed by Alamar-blue assay and increased ROS production measured by flow cytometry. Gene expression of anti-oxidants including GSR, TXNRD1, PRDX1, SOD2 and MT3 was upregulated. BNIP3 expression was increased 2200-fold in RA-FLS after SMV/TLR2 treatment pointing to apoptosis as a cause of observed cytotoxicity. Apoptosis increased in both cell lines with SMV to 25%. Akt decreased dose-dependently in RA FLS assessed by western blots. IP-1, IP-2 and IP3 decreased with SMV/TLR2 treatment indicating cell survival while IL-6 increased dose-dependently. Thus, SMV induces apoptosis in FLS by upregulating BNIP3 and inhibiting Akt. FLS react to survive by increasing IL-6, decreasing IP-1 and IP-2 and upregulating anti-oxidant genes. SMV has immunomodulatory properties and may be used in RA as adjunctive therapy in combination with other more potent disease-modifying medications.

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Section: Resultsmentioning

confidence: 57%

Immunomodulatory effects of Simvastatin in Toll-like receptor-2 stimulated Rheumatoid arthritis synoviocytes

Saeed

Al-Karakooly

Ali

et al. 2022

Preprint

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“…Statins profoundly decrease the expression of osteoarthritic-speciWc matrix metalloproteinases, proteolytic peptidases responsible for tissue remodeling and protein degradation, and induce activated Wbroblast-like synoviocyte apoptosis, eVects that contribute to sustained joint integrity [62][63][64][65].…”

Section: Osteoarthritismentioning

confidence: 99%

The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in rheumatologic disorders: a comprehensive review

2011

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The hydroxy-methyl-glutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment for hyperlipidemia. They have also demonstrated a benefit in a variety of other disease processes, including a wide range of rheumatologic disorders. These secondary actions are known as pleiotropic effects. Our paper serves as a focused and updated discussion on the pleiotropic effects of statins in rheumatologic disorders and emphasizes the importance of randomized, placebo-controlled trials to further elucidate this interesting phenomenon.

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

et al. 2012

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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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Simvastatin Induces Apoptosis of Fibroblast-Like Synoviocytes~!2009-02-16~!2009-03-24~!2009-09-07~!

Cited by 7 publications

References 34 publications

Immunomodulatory effects of Simvastatin in Toll-like receptor-2 stimulated Rheumatoid arthritis synoviocytes

Immunomodulatory effects of Simvastatin in Toll-like receptor-2 stimulated Rheumatoid arthritis synoviocytes

The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in rheumatologic disorders: a comprehensive review

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

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