The mitochondrial inhibitor oligomycin induces an inflammatory response in the rat knee joint

Abstract

BackgroundRecent findings support a connection between mitochondrial dysfunction and activation of inflammatory pathways in articular cells. This study investigates in vivo in an acute model whether intra-articular administration of oligomycin, an inhibitor of mitochondrial function, induces an oxidative and inflammatory response in rat knee joints.MethodsOligomycin was injected into the rat left knee joint on days 0, 2, and 5 before joint tissues were obtained on day 6. The right knee joint served as control. Results were evaluated by macroscopy and histopathology and by measuring cellular and mitochondrial reactive oxygen species (ROS), 4-hydroxy-2-nonenal (4-HNE, a marker of lipid peroxidation), nuclear factor erythroid 2-related factor 2 (Nrf2), and CD68 (macrophages) and chemokine levels. The marker of mitochondrial mass COX-IV was also evaluated.ResultsThe macroscopic findings showed significantly greater swelling in oligomycin-injected knees than in control knees. Likewise, the histological score of synovial damage was also increased significantly. Immunohistochemical studies showed high expression of IL-8, coinciding with a marked infiltration of polymorphonuclears and CD68+ cells in the synovium. Mitochondrial mass was increased in the synovium of oligomycin-injected joints, as well as cellular and mitochondrial ROS production, and 4-HNE. Relatedly, expression of the oxidative stress-related transcription factor Nrf2 was also increased. As expected, no histological differences were observed in the cartilage; however, cytokine-induced neutrophil chemoattractant-1 mRNA and protein expression were up-regulated in this tissue.ConclusionsMitochondrial failure in the joint is able to reproduce the oxidative and inflammatory status observed in arthritic joints.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-017-1621-2) contains supplementary material, which is available to authorized users.

Intraarticular Administration Effect of Hydrogen Sulfide on an In Vivo Rat Model of Osteoarthritis

“…Likewise, we observed that animals under H 2 S treatment showed an upregulated expression of Nrf-2, NQO1 and HO-1, suggesting that the activation of this signaling pathway could be involved in the antioxidant effect of H 2 S. These findings are in accordance with the fact that the downregulation of Nrf-2/HO-1 signaling increases OA severity, whereas its induction elicits protective actions in this pathology [ 59 , 60 ]. Nonetheless, we and other authors observed an upregulation of Nrf-2 levels in OA joint, likely as an insufficient response against the oxidative stress generated during this articular disorder [ 61 , 62 ]. Additionally, a recent study described that the expression of Nrf-2-regulated detoxicant enzymes, such as HO-1 and NQO1, is significantly increased in MIA-injected mice and that treatment with slow H 2 S-release donors maintains these high levels [ 27 ].…”

Monocyte metabolic reprogramming promotes pro-inflammatory activity and Staphylococcus aureus biofilm clearance

“…We selected oligomycin to reprogram monocytes in this study over other metabolic inhibitors because it is less potent and would dampen but not completely block OxPhos, whereas stronger inhibitors, such as rotenone, are extremely toxic and have been shown to inhibit MF viability and function [51][52][53][54]. In addition, a nanoparticle-directed method was preferred for in vivo administration because of potential toxicity associated with a non-targeted systemic delivery approach [55,56]. In this study, nanoparticles were conjugated with tuftsin to facilitate FcR-mediated uptake in monocytes [36], which are the most abundant mononuclear phagocyte population during S. aureus PJI [12][13][14][15].…”

Mitochondrial dsRNAs activate PKR and TLR3 to promote chondrocyte degeneration in osteoarthritis

“…In particular, we asked whether mitochondrial dysfunction could result in the activation of PKR, which can disrupt cell homeostasis by suppressing translation and initiating apoptotic programs. To trigger mitochondrial dysfunction, we treated SW1353 chondrosarcoma cells with oligomycin A (oligoA) to inhibit ATP synthase of the mitochondrial respiratory chain complexes (MRCs), as described in previous studies 44,45 . Using JC-1 dye, we confirmed that oligoA treatment damages mitochondria, which is reflected in the disruption of mitochondrial membrane potential ( Fig.…”