6-shogaol (enexasogoal) improves experimental knee osteoarthritis exerting a pleiotropic effect over immune innate signaling response in chondrocytes
| Autor: | Paula Gratal, Aránzazu Mediero, Ana Lamuedra, Alejandra Matamoros‐Recio, Carmen Herencia, Gabriel Herrero‐Beaumont, Sonsoles Martín‐Santamaría, Raquel Largo |
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| Přispěvatelé: | Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Fundación Conchita Rábago de Jiménez Díaz, Ministerio de Economía y Competitividad (España), European Commission, Gratal, Paula, Mediero, Aranzazu, Lamuedra, Ana, Matamoros-Recio, Alejandra, Herencia, Carmen, Herrero-Beaumont, Gabriel, Martín-Santamaría, Sonsoles, Largo, Raquel, Gratal, Paula [0000-0003-1622-2065], Mediero, Aranzazu [0000-0002-5368-574X], Lamuedra, Ana [0000-0001-6187-130X], Matamoros-Recio, Alejandra [0000-0003-1563-9408], Herencia, Carmen [0000-0003-0589-4608], Herrero-Beaumont, Gabriel [0000-0002-3241-991X], Martín-Santamaría, Sonsoles [0000-0002-7679-0155], Largo, Raquel [0000-0001-6525-2944] |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | 49 p.-9 fig.-1 tab.-1 graph. abst. Background and purpose: The pathogenesis of osteoarthritis (OA) implicates a low-grade inflammation associated to the activation of the innate immune system. Toll like receptor (TLR) stimulation triggers the release of inflammatory mediators, which aggravate OA severity. The aim was to study the preventive effect of 6-shogaol (6S), a potential TLR4 inhibitor, on the treatment of experimental knee OA. Experimental approach: OA was induced in C57BL6 mice by surgical section of the medial meniscotibial ligament, which received 6S for eight weeks. Cartilage damage, inflammatory mediator presence, and disease markers were assessed in the joint tissues by immunohistochemistry. Computational modelling was used to predict binding modes of 6S into the TLR4/MD2 receptor and its permeability across cellular membranes. Employing LPS-stimulated chondrocytes and MAPK assay, we clarified 6S action mechanisms. Key results: 6S treatment was able to prevent articular cartilage lesions, synovitis, and the presence of pro-inflammatory mediators and disease markers in OA animals. Molecular modelling studies predicted 6S interaction with the TLR4/MD-2 heterodimer in an antagonist conformation through its binding into the MD-2 pocket. In cell culture, we confirmed that 6S reduced LPS-induced TLR4 inflammatory signaling pathways. Besides, MAPK assay demonstrated that 6S directly inhibits the ERK1/2 phosphorylation activity. Conclusion and implications: 6S evoked a preventive action on cartilage and synovial inflammation in OA mice. 6S effect may take place not only by hindering the interaction between TLR4 ligands and the TLR4/MD-2 complex in chondrocytes, but also through inhibition of ERK phosphorylation, implying a pleiotropic effect on different mediators activated during OA, which proposes it as an attractive drug for OA treatment. This work was partially supported by grants from the Instituto de Salud Carlos III (PI16/00991,PI18/00261, PI20/00349) and MICINN (CTQ2017-88353-R). AM’s work was funded by the Instituto de Salud Carlos III through the “Miguel Servet” grant program (CP15/00053). PG and AL were founded by Fundación Conchita Rábago, and AM-R was founded by MINECO through the FPI program (PRE2018-086249). This work is co-funded by Fondo Europeo de Desarrollo Regional (FEDER). |
| Databáze: | OpenAIRE |
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