Vaamonde-García Carlos, Loureiro Jesús, Valcárcel-Ares Marta N, Riveiro-Naveira Romina R, Ramil-Gómez Olalla, Hermida-Carballo Laura, Centeno Alberto, Meijide-Failde Rosa, Blanco Francisco J, López-Armada María J
Aging and Inflammation Research Lab, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias, 15006, A Coruña, Spain.
Tissue Engineering and Cellular Therapy Group, INIBIC, Department of Medicine, Faculty of Health Sciences- UDC, Campus Oza, A Coruña, Spain.
BMC Musculoskelet Disord. 2017 Jun 12;18(1):254. doi: 10.1186/s12891-017-1621-2.
Recent 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.
Oligomycin 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.
The 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.
Mitochondrial failure in the joint is able to reproduce the oxidative and inflammatory status observed in arthritic joints.
最近的研究结果支持线粒体功能障碍与关节细胞炎症信号通路激活之间存在关联。本研究在急性模型中进行体内研究，以探究关节内注射线粒体功能抑制剂寡霉素是否会在大鼠膝关节中引发氧化和炎症反应。
在第0、2和5天向大鼠左膝关节注射寡霉素，于第6天获取关节组织。右膝关节作为对照。通过大体观察、组织病理学以及测量细胞和线粒体活性氧（ROS）、4-羟基壬烯醛（4-HNE，脂质过氧化标志物）、核因子红细胞2相关因子2（Nrf2）、CD68（巨噬细胞）和趋化因子水平来评估结果。还评估了线粒体质量标志物细胞色素C氧化酶亚基IV（COX-IV）。
大体观察结果显示，注射寡霉素的膝关节肿胀明显大于对照膝关节。同样，滑膜损伤的组织学评分也显著增加。免疫组织化学研究显示白细胞介素-8高表达，同时滑膜中有大量多形核细胞和CD68 +细胞浸润。注射寡霉素关节的滑膜中线粒体质量增加，细胞和线粒体ROS生成以及4-HNE也增加。相关地，氧化应激相关转录因子Nrf2的表达也增加。正如预期的那样，在软骨中未观察到组织学差异；然而，该组织中细胞因子诱导的中性粒细胞趋化因子-1的mRNA和蛋白表达上调。
关节中的线粒体功能衰竭能够重现关节炎关节中观察到的氧化和炎症状态。
