Geranylgeranylacetone suppresses hydrogen peroxide-induced apoptosis of osteoarthritic chondrocytes

Osteoarthritis (OA) is a common disease, afflicting many sufferers with both pain and functional disorders. Various therapies have been attempted for OA, but no fully effective treatment has been established yet. Apoptosis of chondrocytes caused by reactive oxygen species (ROS) has been considered important in the pathogenesis of OA. The progression of OA may be prevented by suppressing apoptosis of chondrocytes. Geranylgeranylacetone (GGA) has been used as an anti-ulcer drug in Japan for more than 20 years. Several recent studies have shown that GGA can induce heat shock protein (HSP) and exert cytoprotective actions on a large variety of cells and tissues. In this study, we investigated the effects of GGA on the apoptosis of OA chondrocytes induced by hydrogen peroxide (H2O2). Human isolated OA chondrocytes were cultured in the absence or presence of GGA. Cell viability, caspase 3/7 and 9 activities, HSP70 mRNA and protein expressions were examined, and morphological analyses were conducted after exposure of cells to H2O2 to induce apoptosis. Geranylgeranylacetone dose-dependently reversed the H2O2-induced decrease in cell viability. It was recognized that GGA rendered OA chondrocytes resistant to H2O2-induced apoptosis from Hoechst 33342 staining and TUNEL staining. Caspases 3 and 9 were activated by addition of H2O2, and GGA suppressed this H2O2-induced activation of both caspases. H2O2-induced induction of HSP70 was enhanced in OA chondrocytes by pretreatment with GGA. The results showed that GGA can suppress apoptosis of chondrocytes and enhance production of HSP70. This study is the first, to our knowledge, to demonstrate that GGA protects OA chondrocytes from H2O2-induced apoptosis, at least in part by enhancing HSP70 production. These results indicate that GGA is a potentially useful drug for the treatment of OA.