Acidic environments enhance the inhibitory effect of statins on proliferation of synovial cells

•Statins suppressed the proliferation of synovial cell line SW982 in pH 6.7 medium.•The suppression by statins was weak in typical medium of pH 7.5 used until now.•The suppression by statins was caused by the decrease in protein geranylgeranylation.•Acidic medium is more useful for the development of chemotherapies against RA than alkaline medium.

Many previous studies in animal models and clinical investigations have suggested that statins are useful chemotherapeutics against rheumatoid arthritis, whereas in vitro experiments using synovial cell lines showed no significant effect of statins on cell proliferation until now. Since synovial fluid in rheumatoid joint knee was found to be acidic, we examined the effect of statins on human synovial sarcoma cell line SW982 cells in acidic medium. Statins suppressed the proliferation of SW982 cells at pH 6.7, while the suppression was very weak in pH 7.5 medium. It was shown that the suppression was caused by the decrease in geranylgeranyl diphosphate, suggesting that a geranylgeranylated protein(s) has an essential role in cell proliferation of SW982 cells under acidic conditions. Our present data clearly implied that statins had high efficacy against SW982 cells in acidic medium whose pH is close to that of rheumatoid arthritis loci in patients. These results lead us to anticipate that screening of chemicals having high therapeutic efficacy in acidic medium promotes the development of new microenvironment-dependent medicines for chemotherapies against rheumatoid arthritis.