SKI306X was previously found to have cartilage protective effects in the experimental
osteoarthritis (OA) model. To investigate the chondro-protective benefits of
SKI306X for its capacity in altering changes in cartilage metabolism and molecular mechanisms of cartilage protective action,
SKI306X is studied in rabbit cartilage explants culture. To investigate the protective effect of
SKI306X on cartilage catabolism, we assessed
collagen degradation in rabbit cartilage explants treated with
interleukin-1alpha up to 3 weeks. To examine the reaction mechanism,
matrix metalloproteinase (
MMPs) were investigated by fluorimetric and Western blotting analysis. In addition, its effects on the activation process of
proenzyme MMP-3 were determined by
gelatin zymography.
SKI306X significantly inhibited
collagen degradation and inhibited the activities of several
MMPs. Total
MMPs activities in cultured medium were substantially increased in the third week at the time of
collagen degradation with the absence of SKI306. However, the introduction of
SKI306X decreased
MMPs activities in cultured medium. Furthermore, Western blotting analysis proved that these inhibitory effects of this
drug were the result of inhibiting
MMPs expression.
SKI306X also inhibited the activation of
proenzyme MMP-3 to the active form of MMP-3. These results indicate that
SKI306X inhibits matrix degradation by down regulating
MMPs expression and secretion, inhibition of
MMPs activity, and inhibiting activation of MMP-3 during the
collagen breakdown process.