TNF-[alpha] increases the expression of inflammatory factors in synovial fibroblasts by inhibiting the PI3K/AKT pathway in a rat model of monosodium iodoacetate-induced osteoarthritis

Osteoarthritis is a degenerative disease that often causes patients to experience joint pain and deformity. It has been demonstrated that tumor necrosis factor (TNF)-[alpha] is associated with the progression of osteoarthritis; however, to the best of our knowledge, the mechanisms by which TNF-[alpha] 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-[alpha] 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-[alpha] inhibitor on osteoarthritis. The effects of TNF-[alpha] 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-[alpha], interleukin (IL)-1[beta], IL-17a and IL-8 were upregulated in synovial fibroblasts taken from rats with osteoarthritis compared with normal rats. By contrast, TNF-[alpha] inhibition downregulated IL-1[beta], 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-[alpha] inhibitor downregulated the serum and protein levels of IL-1[beta], IL-17a and IL-8 in rats with osteoarthritis. Furthermore, treatment with the TNF-[alpha] 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-[alpha] inhibitor also inhibited the PI3K/AKT pathway in synovial fibroblasts isolated from rats with osteoarthritis. Treatment with the PI3K inhibitor ameliorated TNF-[alpha]-induced increases in IL-1[beta], IL-17a and IL-8 expression in synovial fibroblasts isolated from rats with osteoarthritis. Furthermore, treatment with the TNF-[alpha] inhibitor decreased inflammation, as well as joint and cartilage destruction in vivo. Taken together, the results of the present study indicate that TNF-[alpha] inhibition may downregulate the expression o