Abstract: BACKGROUND: Knee osteoarthritis is a common clinical degenerative joint disease characterized by chronic inflammation and oxidative stress. Resveratrol has anti-inflammatory and anti-oxidative stress biological effects, and therefore it can be used symptomatically and expected to provide a new strategy for the treatment of knee osteoarthritis.
OBJECTIVE: To investigate the therapeutic effect and mechanism of resveratrol on knee osteoarthritis in rats through the silence information regulator 1 (SIRT1)/forkhead transcription factor O1 (FOXO1) pathway.  
METHODS: Forty Sprague-Dawley rats were randomly divided into control group, model group, low-dose resveratrol group, and high-dose resveratrol group, with 10 rats in each group. Knee osteoarthritis models were established in the model group, low-dose resveratrol group, and high-dose resveratrol group. A mixture of 4% papain solution and 0.3 mol/L cysteine solution (1:1 for 0.5 hours; 20 μL) was injected at 1, 4, and 7 days after modeling. Rats in the low-dose and high-dose resveratrol groups were injected with 25 and 100 mg/kg resveratrol through the articular cavity at 1 day after successful modeling, while those in the control and model groups were injected with equivalent volume of physiological saline through the articular cavity. After 28 days of treatment, the maximum knee joint activity was measured; the levels of oxidative stress indicators and inflammatory factors in the synovial fluid of the knee joint were analyzed by radioimmunoassay and ELISA; the content of collagen fibers in the knee joint was analyzed by safranin O-fast green staining; the degree of arthritic lesions was analyzed using the Mankin histological score; and the levels of SIRT1 and FOXO1 in the knee joint were detected by western blot assay.
RESULTS AND CONCLUSION: Compared with the model group, the maximum knee flexion and extension angles of rats significantly increased in the low-dose and high-dose resveratrol groups, and were significantly higher in the high-dose group than the low-dose group (P < 0.05). Compared with the model group, the levels of superoxide dismutase and glutathione peroxidase in the knee joint fluid of rats significantly increased in the low-dose and high-dose resveratrol groups. The level of malondialdehyde significantly decreased in both resveratrol groups, and the level in the high-dose resveratrol group was significantly better than that in the low-dose resveratrol group (P < 0.05). Compared with the model group, the low-dose and high-dose resveratrol groups showed a significant decrease in the levels of interleukin 1β, interleukin 6 and tumor necrosis factor α in the knee joint fluid of rats, and the levels of these inflammatory factors were significantly lower in the high-dose resveratrol group than the low-dose resveratrol group (P < 0.05). Compared with the model group, the content of collagen fibers in the knee joint was significantly increased in both resveratrol groups, and the high-dose resveratrol group showed a higher content of collagen fibers than the low-dose resveratrol group (P < 0.05). Compared with the model group, the expression level of SIRT1 in the knee joints of rats significantly increased in both resveratrol groups, while the level of acetylated FOXO1 significantly decreased (P < 0.05). The magnitude of changes was significantly better in the high-dose group than the low-dose group. To conclude, resveratrol significantly improves the levels of oxidative stress and inflammatory factors in the joint fluid of rats with knee osteoarthritis and alleviates arthritic symptoms in a dose-dependent manner, possibly through the SIRT1/FOXO1 pathway.

Key words: knee osteoarthritis, resveratrol, SIRT1/FOXO1 signaling pathway, inflammation level, oxidative stress