Li Xueyan, Tao Huaqiang, Zhou Jing, Zhang Liyuan, Shi Yi, Zhang Chun, Sun Wen, Chu Miao, Chen Kai, Gu Chengyong, Yang Xing, Geng Dechun, Hao Yuefeng
Anesthesiology Department, Suzhou Municipal Hospital (North District), Nanjing Medical University Affiliated Suzhou Hospital, 242, Guangji Road, Suzhou, Jiangsu, China.
Department of Orthopedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, Jiangsu, China.
Free Radic Biol Med. 2023 Nov 1;208:13-25. doi: 10.1016/j.freeradbiomed.2023.07.019. Epub 2023 Jul 28.
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage injury, hyperplasia of bone and inflammatory lesions of synovium. Monoacylglycerol lipase (MAGL), a member of the α/β hydrolase superfamily, is involved in regulation of injury protection and immune-inflammation response. Autoinflammatory response of the synovium and the release of inflammatory mediators play critical roles in occurrence of early-stage OA. Fibroblast-like synoviocytes (FLSs) are resident mesenchymal cells of the synovial tissue. Considering that MAGL inhibition regulates the inflammatory signaling cascade, it is crucial to ascertain the biological effects and specific mechanisms of MAGL in alleviating inflammatory infiltration of OA FLSs. The aim of this study was to investigate the effect of MAGL on biological function in OA FLSs. Results from in vitro experiments showed that MAGL blockade not only effectively inhibited proliferation, invasion and migration of FLSs, but also downregulated expression of inflammatory-associated proteins. Sequencing results indicated that MAGL inhibition significantly suppressed NOX4-mediated oxidative stress, thus promoting Nrf2 nuclear accumulation and inhibiting generation of intracellular reactive oxygen species (ROS). Attenuation of NOX4 further alleviated redox dysplasia and ultimately improved tumor-like phenotypes, such as abnormal proliferation, migration and migration of FLSs. In vivo results corroborated this finding, with MAGL inhibition found to modulate pain and disease progression in an OA rat model. Collectively, these results indicate that MAGL administration is an ideal therapy treating OA.
骨关节炎（OA）是一种以软骨损伤、骨质增生和滑膜炎症性病变为特征的退行性关节疾病。单酰甘油脂肪酶（MAGL）是α/β水解酶超家族的成员之一，参与损伤保护和免疫炎症反应的调节。滑膜的自身炎症反应和炎症介质的释放在早期OA的发生中起关键作用。成纤维细胞样滑膜细胞（FLSs）是滑膜组织中的常驻间充质细胞。鉴于MAGL抑制可调节炎症信号级联反应，确定MAGL在减轻OA-FLSs炎症浸润中的生物学效应和具体机制至关重要。本研究的目的是探讨MAGL对OA-FLSs生物学功能的影响。体外实验结果表明，MAGL阻断不仅有效抑制了FLSs的增殖、侵袭和迁移，还下调了炎症相关蛋白的表达。测序结果表明，MAGL抑制显著抑制了NOX4介导的氧化应激，从而促进了Nrf2核积累并抑制了细胞内活性氧（ROS）的产生。NOX4的减弱进一步减轻了氧化还原发育异常，最终改善了肿瘤样表型，如FLSs的异常增殖、迁移和侵袭。体内结果证实了这一发现，发现MAGL抑制可调节OA大鼠模型中的疼痛和疾病进展。总之，这些结果表明，给予MAGL是治疗OA的理想疗法。
