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TLR4 Inhibitors Improve Experimental Knee Osteoarthritis

Osteoarthritis is a complex and disabling disease with a high incidence in developed countries, and there is currently no effective treatment. It is characterized by progressive destruction of the articular cartilage (AC), synovitis, and degeneration of the meniscus and ligaments. The pathogenesis of osteoarthritis (OA) involves a low-grade inflammation associated with activation of the innate immune system.
Toll-like receptor (TLR) stimulation triggers the release of inflammatory mediators that exacerbate the severity of OA. The purpose of this study was to explore the preventive effect of a potential TLR4 inhibitor, 6-shogaol (6S), on experimental knee osteoarthritis.
Recently, researchers from the Autonomous University of Madrid published an article entitled "6-shogaol treatment improves experimental knee OA exerting a pleiotropic effect over immune innate signaling response in chondrocytes" in the journal Br J Pharmacol. This study confirmed the preventive effect of 6S on cartilage and synovial inflammation in osteoarthritis mice. The 6S effect may play a role not only by inhibiting the interaction between TLR4 ligand and TLR4/MD-2 complex in chondrocytes, but also by inhibiting the phosphorylation of ERK, suggesting that 6S has pleiotropic effect on different mediators activated during osteoarthritis, which is expected to be an effective drug for the treatment of osteoarthritis.
In this study, the researchers surgically removed the medial meniscus-tibial ligament of C57BL6 mice to establish an osteoarthritis model, and treated with 6S for 8 weeks. Cartilage damage, the presence of inflammatory mediators and disease markers in joint tissue were detected by immunohistochemistry. The computational model was used to predict the binding mode of 6S to TLR4/MD2 receptor and its permeability across cell membranes. Through LPS stimulation of chondrocytes and MAPK experiments, the researchers elucidated the mechanism of action of 6S.
6S treatment was able to prevent articular cartilage damage, synovitis and the presence of pro-inflammatory mediators and disease markers in OA animals. Molecular modeling studies predict that 6S binds to the MD-2 pocket in an antagonist conformation with the TLR4/MD-2 heterodimer. In cell culture, researchers demonstrated that 6S reduced endotoxin-induced TLR4 inflammatory signaling. Furthermore, MAPK experiments showed that 6S directly inhibited the phosphorylation activity of ERK1/2.
Taken together, this study demonstrates that 6S can prevent cartilage destruction and joint inflammation in experimental knee osteoarthritis, hindering the extracellular interaction between TLR4 ligands and TLR4/MD-2. In addition, 6S can inhibit the phosphorylation of ERK in cells. Thus, the compound can exert pleiotropic effects on TLR4 signaling, thereby enhancing its beneficial effects on disease. 6S can be considered as a new treatment option for human osteoarthritis.
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