| Summary: | <p>Abstract</p> <p>Background</p> <p>To study the ability of tepoxalin, a dual inhibitor of cyclooxygenase (COX) and lipoxygenase (LOX) and its active metabolite to reduce the catabolic response of cartilage to cytokine stimulation in an <it>in vitro </it>model of canine osteoarthritis (OA).</p> <p>Grossly normal cartilage was collected post-mortem from seven dogs that had no evidence of joint disease. Cartilage explants were cultured in media containing the recombinant canine interleukin-1<it>β </it>(IL-1<it>β</it>) at 100 ng/ml and recombinant human oncostatin-M (OSM) at 50 ng/ml. The effects of tepoxalin and its metabolite were studied at three concentrations (1 × 10<sup>-5</sup>, 1 × 10<sup>-6 </sup>and 1 × 10<sup>-7 </sup>M). Total glycosaminoglycan (GAG) and collagen (hydroxyproline) release from cartilage explants were used as outcome measures of proteoglycan and collagen depletion respectively. PGE<sub>2 </sub>and LTB<sub>4 </sub>assays were performed to study the effects of the drug on COX and LOX activity.</p> <p>Results</p> <p>Treatment with IL-1<it>β </it>and OSM significantly upregulated both collagen (p = 0.004) and proteoglycan (p = 0.001) release from the explants. Tepoxalin at 10<sup>-5 </sup>M and 10<sup>-6 </sup>M caused a decrease in collagen release from the explants (p = 0.047 and p = 0.075). Drug treatment showed no effect on GAG release. PGE<sub>2 </sub>concentration in culture media at day 7 was significantly increased by IL-1<it>β </it>and OSM and treatment with both tepoxalin and its metabolite showed a trend towards dose-dependent reduction of PGE<sub>2 </sub>production. LTB<sub>4 </sub>concentrations were too low to be quantified. Cytotoxicity assays suggested that neither tepoxalin nor its metabolite had a toxic effect on the cartilage chondrocytes at the concentrations and used in this study.</p> <p>Conclusion</p> <p>This study provides evidence that tepoxalin exerts inhibition of COX and can reduce <it>in vitro </it>collagen loss from canine cartilage explants at a concentration of 10<sup>-5 </sup>M. We can conclude that, in this model, tepoxalin can partially inhibit the development of cartilage degeneration when it is available locally to the tissue.</p>
|
|---|
