The activation and proliferation of synovial cells, which is thought to play a key role in RA, may be exacerbated when apoptosis of synovial cells is either insufficient or resistant to treatment. In the first study to demonstrate whether statins can induce apoptosis in synovial cells of RA patients, researchers led by Takao Nagashima of Jichi Medical School, Tochigi, Japan measured the effect in vitro of two statins, fluvastatin (a fat-soluble statin) and pravastatin (a water-soluble statin) on human synovial cells from patients with RA and osteoarthropathy. "In the present study, we demonstrated that fluvastatin induced apoptosis in synoviocytes from patients with RA, but not in those from patients with osteoarthropathy, suggesting that the apoptotic effect of fluvastatin is a mechanism for suppression of inflammatory arthritis such as RA by statins," the authors state.
They were also able to determine the pathway by which apoptosis occurred: the inhibition of protein geranygeranylation (a process involving the metabolism of certain proteins that is essential for proper cell function, including the survival of vascular smooth muscle cells) was shown to be necessary for apoptosis to occur in these cells. Specifically, the pathway involves inhibition of the geranylgeranylated protein RhoA/RhoA kinase, which has already been shown to be involved in apoptosis.
The researchers point out that the in vitro concentrations they used of the statins were much higher than amounts that would normally be prescribed to patients. Although they note that it is possible that in the human body relatively low, but sustained, blood levels of statins would exert an effect similar to that seen in vitro with higher concentrations and short incubation times, they acknowledge that the therapeutic effect of fluvastatins in patients remains to be determined.
The authors conclude: 'The induction of apoptosis in RA synovial cells by fluvastatin and the biologic antiatherosclerotic properties of the statins suggest that they may turn out to be ideal therapeutic agents in RA. Based on these results, we propose that the statins warrant clinical trials as potential modifiers of RA."
Article: "Apoptosis of Rheumatoid Synovial Cells by Statins Through the Blocking of Protein Geranlgeranylation," Takao Nagashima, Hitoaki Okazaki, Kazuo Yudoh, Hiroaki Matsuno, Seiji Minota, Arthritis & Rheumatism, February 2006; 54:2; pp. 579-586.