Celecoxib decreases the production of cytokines by osteoarthritic cartilage and synovium without affecting cartilage matrix degradation

Abstract

Purpose: Recently, we reported a coculture model with osteoarthritic cartilage and synovial tissue that is more representative for osteoarthritis (OA) and useful to study mechanisms of action of OA therapies. Celecoxib, a COX-2 inhibitor, is frequently used for the treatment of osteoarthritis. However, its effect on cartilage metabolism has been the subject of much debate. Moreover, it is unclear how celecoxib affects the levels of soluble mediators in the joint. In the current study we investigate the effect of celecoxib on cartilage matrix turnover and the secretion of soluble mediators by cartilage and synovium in a coculture of OA cartilage and synovial tissue. Methods: OA cartilage and OA synovium explants were cultured alone or in coculture for 21 days with the addition of celecoxib at 0.1, 1.0 and 10 μM. To study cartilage matrix turnover glycosaminoglycan (GAG) content, production and release were determined. ELISAs for IL-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-13, OSM, MCP1, NGF, leptin, adiponectin and PGE2 were performed on conditioned medium of day 4. For statistical analysis, univariate analysis of variance was performed, with a randomized block design to correct for inter-donor variability. P values < 0.05 were considered significantly different. Results: Both osteoarthritic cartilage and synovial tissue produced PGE2 and celecoxib inhibited the production in a dose dependent manner (P < 0.05; Fig. 1a). Celecoxib, irrespective of the concentration used, did not show an effect on GAG content, release and production in the coculture (Fig. 1b). Celecoxib at a concentration of 10 μM decreased the production of IL-1α, IL-1ß, IL-6, IL-10, OSM and NGF (P < 0.05). No effect was seen on leptin, adiponectin, IL-8 and MCP1. IL-13 and IL-4 were not detected (Fig. 1c). Conclusion: This study shows that celecoxib decreased the production of multiple soluble mediators associated with inflammation and pain in OA. Although the production of multiple pro-inflammatory cytokines and PGE2 was decreased, no effect on cartilage matrix turnover was seen. The decreased production of mediators associated with pain in OA, such as NGF, IL-6 and PGE2 is in line with the effect on pain observed in patients treated with celecoxib.