title: GW9508, a free fatty acid receptor agonist, specifically induces cell death in bone resorbing precursor cells through increased oxidative stress from mitochondrial origin.
abstract: GW9508 is a free fatty acid receptor agonist able to protect from ovariectomy-induced bone loss in vivo thought inhibition of osteoclast differentiation in a G-coupled Protein Receptor 40 (GPR40)-dependent way. In this study, we questioned whether higher doses of GW9508 may also influence resorbing cell viability specifically. Interestingly, GW9508 at 100 µM altered osteoclast precursor (OcP) viability while it had positive effects on osteoblastic precursors suggesting an activity dependent on the cell lineage. According to 7-AAD/Annexin-V staining, induced OcP cell death was found to be associated with necrosis mechanisms. Consistently, GW9508 led to a sustained establishment of oxidative stress from mitochondrial origin. In contrast to previous observations on osteoclast differentiation inhibition, OcP viability targeted by high doses of GW9508 appeared to be independent of GPR40 involvement. Although mediating structures remain to be determined, our data demonstrate for the first time that this fatty acid receptor agonist driving OcP specific cell death may now open new perspectives regarding therapeutic strategies in osteolytic disorders.
authors: INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France.
authors: Claire
authors: C
authors: Philippe
authors: Fabien
authors: F
authors: Wauquier
authors: Laurent
authors: L
authors: Léotoing
authors: Véronique
authors: V
authors: Coxam
authors: Yohann
authors: Y
authors: Wittrant
mesh_terms: D001862:Bone Resorption / Q000378:metabolism*; D001842:Bone and Bones / Q000166:cytology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism; D008744:Methylamines / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology*; D018384:Oxidative Stress / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology*
chemical_list: D005227:Fatty Acids; C515630:GW9508; D008744:Methylamines; D011422:Propionates
keywords: Bone; Cell death; Free fatty acid receptor agonist; Oxidative stress