1. 6-Shogaol (enexasogoal) treatment improves experimental knee osteoarthritis exerting a pleiotropic effect over immune innate signalling responses in chondrocytes.
- Author
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Gratal, Paula, Mediero, Aránzazu, Lamuedra, Ana, Matamoros‐Recio, Alejandra, Herencia, Carmen, Herrero‐Beaumont, Gabriel, Martín‐Santamaría, Sonsoles, Largo, Raquel, Matamoros-Recio, Alejandra, Herrero-Beaumont, Gabriel, and Martín-Santamaría, Sonsoles
- Subjects
CARTILAGE cells ,KNEE osteoarthritis ,LIPOPOLYSACCHARIDES ,PHENOLS ,INFLAMMATION ,MOLECULAR models ,CELL receptors ,RESEARCH funding ,INFLAMMATORY mediators ,ANIMALS ,MICE - Abstract
Background and Purpose: The pathogenesis of osteoarthritis implicates a low-grade inflammation associated to the innate immune system activation. Toll like receptor (TLR) stimulation triggers the release of inflammatory mediators, which aggravate osteoarthritis. We studied the preventive effect of 6-shogaol, a potential TLR4 inhibitor, on the treatment of experimental knee osteoarthritis.Experimental Approach: Osteoarthritis was induced in C57BL6 mice by surgical section of the medial meniscotibial ligament, which received 6-shogaol for eight weeks. Cartilage damage, inflammatory mediator presence and disease markers were assessed in joint tissues by immunohistochemistry. Computational modelling was used to predict binding modes of 6-shogaol into the TLR4/MD2 receptor and its permeability across cellular membranes. Employing LPS-stimulated chondrocytes and MAPK assay, we elucidated 6-shogaol action mechanisms.Key Results: 6-Shogaol treatment prevented articular cartilage lesions, synovitis and the presence of pro-inflammatory mediators, and disease markers in osteoarthritis animals. Molecular modelling studies predicted 6-shogaol 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 6-shogaol reduced LPS-induced TLR4 inflammatory signalling pathways. Besides, MAPK assay demonstrated that 6-shogaol directly inhibits the ERK1/2 phosphorylation activity.Conclusion and Implications: 6-Shogaol evoked a preventive action on cartilage and synovial inflammation in osteoarthritis mice. 6-shogaol 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 osteoarthritis, which proposes it as an attractive drug for osteoarthritis treatments. [ABSTRACT FROM AUTHOR]- Published
- 2022
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