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.
Highlights
Recent findings support a connection between mitochondrial dysfunction and activation of inflammatory pathways in articular cells
Multiple studies indicate that reactive oxygen species (ROS) production is increased in rheumatic diseases (e.g., rheumatoid arthritis (RA) or osteoarthritis (OA)) leading to oxidative stress which may contribute to articular damage and to the chronicity of these pathologies
The aim of this study was to analyze in vivo in an acute model whether mitochondrial defects can reproduce the oxidative and inflammatory status observed in arthritic joints
Summary
Recent findings support a connection between mitochondrial dysfunction and activation of inflammatory pathways in articular cells. Multiple studies indicate that reactive oxygen species (ROS) production is increased in rheumatic diseases (e.g., rheumatoid arthritis (RA) or osteoarthritis (OA)) leading to oxidative stress which may contribute to articular damage and to the chronicity of these pathologies. Oxidative damage to mitochondria may lead to respiratory chain dysfunction, which results in increased ROS levels, leading to a vicious cycle of oxidative stress [10]. Pro-inflammatory mediators, which are highly produced in these disorders, may alter mitochondrial function of human synoviocytes and chondrocytes [22, 26,27,28], reinforcing the strong link between mitochondrial defects and oxidative stress and inflammation [29]
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