This study was designed to compare the long-term effects (12 days) of nonsteroidal anti-inflammatory drugs (NSAID) on the metabolism of human chondrocytes cultured in alginate beads.
Enzymatically isolated osteoarthritic (OA) chondrocytes were cultured in alginate beads in a well-defined culture medium (DMEM +ITS+) for 12 days. Interleukin-6 and -8 (IL-6, IL-8), stromelysin (MMP-3) and aggrecan (AGG) productions were assayed by specific enzyme amplified sensitivity immunoassays (EASIA), and prostaglandin E2 (PGE2) production by a specific radioimmunoassay. All NSAID were tested at the mean peak plasmatic concentration (Cmax) obtained after oral administration of a therapeutic dose. The Cmax used in this study were 7.5 mg/ml for aceclofenac (ACECLO), 1.4 mg/ml for diclofenac (DICLO), 2 mg/ml for indomethacin (INDO), 3 mg/ml for nimesulide (NIM),1 mg/ml for rofecocib (ROFE), 0.7 mg/ml for celecoxib (CELE), 7 mg/ml for piroxicam (PIROX), and 25 mg/ml for ibuprofen (IBUP).
At the therapeutic concentration, all NSAID tested fully blocked PGE2 production. Interestingly, ACECLO, DICLO, INDO, NIM and IBUP significantly inhibited both basal and IL-1b-stimulated IL-6 production, whereas ROFE, CELE and PIROX had no significant effects. No NSAID showed significant effects on basal and IL-1b-stimulated IL-8 production, excepted CELE and IBUP which slightly increased basal IL-8 production. ACECLO and INDO increased by 25% AGG content in the alginate beads, while the other NSAID were without significant effect. Furthermore, none NSAID were able to modify the inhibitory effect of IL-1b on AGG production. Finally, NSAID did not modify MMP-3 production.
From this study, we can conclude that the mechanism of action of NSAID seems to be multifactorial and not limited to the inhibition of cyclooxygenases. Furthermore, in our culture conditions, at the Cmax and by comparison with other NSAID ACECLO and INDO show a advantageous profile of activity. They fully block PGE2 production, inhibit IL-6 synthesis and increase aggrecan synthesis. These effects would appear to be advantageous for the long-term treatment of chronic joint diseases such as osteoarthritis.