Synergistic therapeutic effect of parecoxib and ilomastat combination in osteoarthritis via inhibition of IL-17/PI3K/AKT/NF-κB activity

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BACKGROUND: Osteoarthritis is a degenerative disease, and current drug treatment is to give nonsteroidal anti-inflammatory drugs to relieve symptoms. The anti-inflammatory ability of parecoxib and ilomastat has been confirmed, but the synergistic effect of combined administration in osteoarthritis has not been clear. METHODS: Mouse primary chondrocytes stimulated with IL-1β were cultured. The expression levels of inflammatory cytokines and matrix metalloproteinases were investigated by western blotting, quantitative real-time polymerase chain reaction and ELISA. The effects of parecoxib and ilomastat on chondrocyte apoptosis were evaluated by flow cytometry. In addition, the rat model of osteoarthritis was established by meniscal instability, and the morphological changes of cartilage and the expression levels of related molecules were monitored using Safranin O-Fast green and immunohistochemical staining after intra-articular injection of parecoxib, ilomastat, and the combination of the two. RESULTS: In vitro experiments showed that the combined administration of parecoxib and ilomastat more effectively inhibited the expression of proinflammatory factors and matrix metalloproteinases compared with single drug administration. The combined drug treatment could more effectively inhibit IL-1β-induced chondrocyte apoptosis. The combined drug treatment alleviated the progression of osteoarthritis by inhibiting the IL-17/PI3K/AKT/NF-κB pathway. In addition, in vivo experiments showed that the combined administration could improve the further deterioration of the osteoarthritis rat model. CONCLUSIONS: The combined administration of parecoxib and ilomastat to inhibit IL-17/PI3K/AKT/NF-κB transduction is beneficial to reduce the infiltration of inflammatory factors and matrix metalloproteinases in osteoarthritis.

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