SKI306X Suppresses Cartilage Destruction and Inhibits the Production of Matrix Metalloproteinase in Rabbit Joint Cartilage Explant Culture

J Pharmacol Sci. 2005 Jul;98(3):298-306. doi: 10.1254/jphs.fpj04058x.

Abstract

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.

MeSH terms

  • Animals
  • Blotting, Western
  • Cartilage, Articular / drug effects*
  • Cartilage, Articular / metabolism
  • Collagen / metabolism
  • Collagenases / biosynthesis
  • Drugs, Chinese Herbal / pharmacology*
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 3 / biosynthesis
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / antagonists & inhibitors*
  • Metalloendopeptidases / biosynthesis
  • Rabbits

Substances

  • Drugs, Chinese Herbal
  • Matrix Metalloproteinase Inhibitors
  • SKI 306X
  • Collagen
  • Collagenases
  • Matrix Metalloproteinase 13
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3