title: Deficiency of G-protein coupled receptor 40, a lipid-activated receptor, heightens in vitro- and in vivo-induced murine osteoarthritis.
abstract: Osteoarthritis (OA) is an age-related degenerative joint disease. To date, its management is focused on symptoms (pain and inflammation). Studies suggest that fatty acids can reduce the expression of inflammatory and catalytic mediators, and improve in vivo joint function. Free fatty acid receptors (FFARs) such as G-protein coupled receptor 40 (GPR40) are proposed as attractive therapeutic targets to counteract inflammation and cartilage degradation observed in OA. This study aims to elucidate the involvement of GPR40 in OA. In this study, we used an in vitro model of OA, and surgically induced OA by ligament transection and partial meniscectomy in wild-type and GPR40 deficient mice. OA phenotype was investigated in vivo by histology and genes expression. We demonstrate that IL-1β-treated GPR40(-/-) chondrocytes secret more inflammatory mediators (nitric oxide, interleukin-6, prostaglandin E2) and active catabolic enzymes (metalloproteinase-2, -9 [MMP-2, MMP-9]), and show decreased anabolism (glycoaminoglycan) compared to GPR40(+/+) cells. In accordance with these results, we show that GPR40(-/-) mice exhibit an aggravated OA-induced phenotype characterized by higher tidemark exposure, frequency of osteophyte formation and subchondral bone sclerosis. Altogether our results demonstrate that GPR40 deficiency leads to an extended OA phenotype, providing evidence that increasing GPR40 activity, by natural or synthetic ligands, could be a new strategy in the management of OA.
authors.affiliation: Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, F-63000 Clermont-Ferrand, France INRA, UNH, CRNH Auvergne, F-63000 Clermont-Ferrand, France laurent-emmanuel.monfoulet@clermont.inra.fr.
authors.forename: Laurent-Emmanuel
authors.initials: LE
authors.lastname: Monfoulet
authors.affiliation: Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, F-63000 Clermont-Ferrand, France INRA, UNH, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Philippe
authors.affiliation: Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, F-63000 Clermont-Ferrand, France INRA, UNH, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mercier
authors.affiliation: Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, F-63000 Clermont-Ferrand, France INRA, UNH, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Coxam
authors.affiliation: Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, F-63000 Clermont-Ferrand, France INRA, UNH, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Wittrant
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology*; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: C473036:Ffar1 protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: Free fatty acid receptor (FFAR); G-protein coupled receptor 40; natural therapy; osteoarthritis