Abstract
Osteoarthritis (OA) is mainly manifested by joint pain, stiffness and mobility disorder, which is the main cause of pain and disability in middle-aged and elderly people. In this study, we aimed to explore the role and mechanism of 8-Methoxypsoralen (8-MOP) in the OA model both in vitro and in vivo. The rat chondrocytes were treated with IL-1β, and the proliferation, apoptosis, inflammatory reactions and oxidative stress responses were determined after treatment with different concentrations of 8-MOP. Real-time quantitative polymerase chain reaction (qRT-PCR) and/or Western blot were implemented to check the AMPK/SIRT1/NF-κB expression in chondrocytes. The NF-κB activity was determined by dual luciferase experiment. The pain threshold of OA rat model dealt with 8-MOP and/or the SIRT1 inhibitor EX527 was measured. Our results revealed that 8-MOP evidently reduced IL-1β-mediated apoptosis and inhibition of proliferation, and mitigated the expression of inflammatory cytokines and oxidative stress factors in chondrocytes. Additionally, 8-MOP promoted phosphorylated level of AMPKα, enhanced SIRT1 expression and inhibited the phosphorylation of NF-κB. After treatment with EX527, 8-MOP-mediated protective effects on chondrocytes were mostly reversed. In vivo, 8-MOP obviously improved the pain threshold in the OA rat model and reduced the injury and apoptosis of chondrocytes in the joints. In addition, 8-MOP relieved inflammatory and oxidative stress responses in the articular cartilage via enhancing SIRT1 and repressing NF-κB activation. After the treatment with EX527, the 8-MOP-mediated protective effects were distinctly weakened. In summary, our study testified that 8-MOP alleviates pain, inflammatory and oxidative stress responses in OA rats through the SIRT1/NF-κB pathway, which is expected to become a new reagent for clinical treatment of OA.
Highlights
Osteoarthritis (OA) is a prevalent form of chronic joint inflammation, and the incidence of which may increase with the extension of human life expectancy (Pereira et al, 2015)
The results showed that compared with the IL-1β or IL-1β + 8-MOP (40 μM) group, EX527 enhanced the release of some cytokines (IL-6, tumor necrosis factor (TNF)-α, IL18) and oxidative stree mediator MDA, while the release of SOD and GSH-PX was reduced (p < 0.05, Figures 4D–G)
Under the treatment of 8-MOP, the expression of p-AMPKαand SIRT1 was enhanced and the expression of p-NF-κB p65 in the whole cells and nuclear as well as acetylated NF-κB p65 was all reduced in the OA + 8-MOP group (p < 0.05, Figure 7B). These results showed that 8-MOP facilitated the AMPK/SIRT1 and downregulated NF-κB pathway expression in OA rats
Summary
Osteoarthritis (OA) is a prevalent form of chronic joint inflammation, and the incidence of which may increase with the extension of human life expectancy (Pereira et al, 2015). Current therapies for OA are mainly related to intraarticular, physical, alternative, and surgical therapy (Abramoff and Caldera, 2020). Many agents have been found to be effective in relieving the pain in OA patients, those drugs include analgesics such as non-steroidal anti-inflammatory drugs, corticosteroids such as glucocorticoids, hyaluronic acid and local anesthetics (Rychel, 2010; Richards et al, 2016; Jones et al, 2019). The limitations such as side effects have restrained their clinical application. It is indispensable to explore new therapeutic agents for the treatment of OA
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