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6-shogaol treatment improves experimental knee OA exerting a pleiotropic effect over immune innate signaling response in chondrocytes
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  • Paula Gratal,
  • Aranzazu Mediero,
  • Ana Lamuedra,
  • Alejandra Matamoros-Recio,
  • Gabriel Herrero-Beaumont,
  • Sonsoles Martín-Santamaría,
  • Raquel Largo
Paula Gratal
Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz

Corresponding Author:[email protected]

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Aranzazu Mediero
Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz
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Ana Lamuedra
Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz
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Alejandra Matamoros-Recio
Centro de Investigaciones Biológicas Margarita Salas, CIB-CSIC
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Gabriel Herrero-Beaumont
Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz
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Sonsoles Martín-Santamaría
Centro de Investigaciones Biológicas Margarita Salas, CIB-CSIC
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Raquel Largo
Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz
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Abstract

Background: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. Experimentalapproach: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 modeling 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. 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 modeling 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: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.
21 Jul 2021Submitted to British Journal of Pharmacology
22 Jul 2021Submission Checks Completed
22 Jul 2021Assigned to Editor
20 Aug 2021Reviewer(s) Assigned
17 Dec 2021Review(s) Completed, Editorial Evaluation Pending
07 Jan 2022Editorial Decision: Revise Minor
06 Apr 20221st Revision Received
09 Apr 2022Submission Checks Completed
09 Apr 2022Assigned to Editor
29 Apr 2022Reviewer(s) Assigned
16 May 2022Review(s) Completed, Editorial Evaluation Pending
14 Jun 2022Editorial Decision: Accept
09 Aug 2022Published in British Journal of Pharmacology. 10.1111/bph.15908