Inhibition of protein geranylgeranylation induces apoptosis in synovial fibroblasts |
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Authors: | Connor Alison M Berger Stuart Narendran Aru Keystone Edward C |
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Institution: | (1) The Wellesley Toronto Arthritis and Immune Disorder Research Centre, 101 College St. Toronto, M5G 1L7 Ontario, Canada;(2) Southern Alberta Children's Cancer Program, Alberta Children's Hospital, 1820 Richmond Road SW Calgary, T2T 5C7 Alberta, Canada;(3) The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mount Sinai Hospital, 60 Murray Street, M5T 3L9 Toronto, Ontario, Canada |
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Abstract: | Statins, competitive inhibitors of hydroxymethylglutaryl-CoA reductase, have recently been shown to have a therapeutic effect
in rheumatoid arthritis (RA). In RA, synovial fibroblasts in the synovial lining, are believed to be particularly important
in the pathogenesis of disease because they recruit leukocytes into the synovium and secrete angiogenesis-promoting molecules
and proteases that degrade extracellular matrix. In this study, we show a marked reduction in RA synovial fibroblast survival
through the induction of apoptosis when the cells were cultured with statins. Simvastatin was more effective in RA synovial
fibroblasts than atorvastatin, and both statins were more potent on tumor necrosis factor-α-induced cells. In contrast, in
osteoarthritis synovial fibroblasts, neither the statin nor the activation state of the cell contributed to the efficacy of
apoptosis induction. Viability of statin-treated cells could be rescued by geranylgeraniol but not by farnesol, suggesting
a requirement for a geranylgeranylated protein for synovial fibroblast survival. Phase partitioning experiments confirmed
that in the presence of statin, geranylgeranylated proteins are redistributed to the cytoplasm. siRNA experiments demonstrated
a role for Rac1 in synovial fibroblast survival. Western blotting showed that the activated phosphorylated form of Akt, a
protein previously implicated in RA synovial fibroblast survival, was decreased by about 75%. The results presented in this
study lend further support to the importance of elevated pAkt levels to RA synovial fibroblast survival and suggest that statins
might have a beneficial role in reducing the aberrant pAkt levels in patients with RA. The results may also partly explain
the therapeutic effect of atorvastatin in patients with RA. |
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