Abstract
Osteoarthritis is a degenerative disease that often causes patients to experience joint pain and deformity. It has been demonstrated that tumor necrosis factor (TNF)-α is associated with the progression of osteoarthritis; however, to the best of our knowledge, the mechanisms by which TNF-α simulates the progression of osteoarthritis and the signaling pathway(s) it influences remain unknown. Therefore, the aim of the present study was to investigate the therapeutic effects of TNF-α inhibitor in an iodoacetate-induced rat model of osteoarthritis and identify its potential mechanisms of action. Western blotting, ELISA and histological analyses were performed to assess the effects of the TNF-α inhibitor on osteoarthritis. The effects of TNF-α and phosphoinositide 3-kinase (PI3K) inhibition on synovial fibroblasts isolated from rats with osteoarthritis were tested in vitro. Furthermore, the expression of various inflammatory cytokines and the PI3K/protein kinase B (AKT) signaling pathway were assessed in vitro. The results indicated that the inflammatory factors TNF-α, interleukin (IL)-1β, IL-17a and IL-8 were upregulated in synovial fibroblasts taken from rats with osteoarthritis compared with normal rats. By contrast, TNF-α inhibition downregulated IL-1β, IL-17a and IL-8 expression in synovial fibroblasts in vitro. The PI3K/AKT pathway was also upregulated in synovial fibroblasts harvested from rats with osteoarthritis compared with that in normal rats. It was demonstrated that treatment with the TNF-α inhibitor downregulated the serum and protein levels of IL-1β, IL-17a and IL-8 in rats with osteoarthritis. Furthermore, treatment with the TNF-α inhibitor also decreased matrix metalloproteinase (MMP)-3, MMP-9, vascular endothelial growth factor and ADAMTS4 expression in synovial fibroblasts isolated from rats with osteoarthritis. Treatment with the TNF-α inhibitor also inhibited the PI3K/AKT pathway in synovial fibroblasts isolated from rats with osteoarthritis. Treatment with the PI3K inhibitor ameliorated TNF-α-induced increases in IL-1β, IL-17a and IL-8 expression in synovial fibroblasts isolated from rats with osteoarthritis. Furthermore, treatment with the TNF-α inhibitor decreased inflammation, as well as joint and cartilage destruction in vivo. Taken together, the results of the present study indicate that TNF-α inhibition may downregulate the expression of inflammatory factors in synovial fibroblasts, suggesting that TNF-α inhibition may be a novel method for treating osteoarthritis by downregulating the PI3K/AKT signaling pathway.