Chen Guang-Yao, Liu Xiao-Yu, Yan Xue-Er, Yu XinBo, Liu Yi, Luo Jing, Tao Qing-Wen
Department of TCM Rheumatology, China-Japan Friendship Hospital, Beijing, People's Republic of China.
Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, China-Japan Friendship Hospital, Beijing, People's Republic of China.
J Inflamm Res. 2023 Sep 20;16:4123-4140. doi: 10.2147/JIR.S418345. eCollection 2023.
Previous clinical studies have found that total flavonoids of Rhizoma Drynariae (TFRD) have a good therapeutic effect on osteoarthritis (OA), but its therapeutic mechanism needs further research.
OA rat model was established by Hulth method and was intervened by TFRD. Pathological assessments were conducted to assess the protective effect of TFRD on cartilage. Serum metabolomics and network pharmacology were detected to predict the mechanism of TFRD treating OA. In further experiments, molecular biology experiment was carried out to confirm the predicted mechanisms in vivo and in vitro.
TFRD can effectively reduce chondrocyte apoptosis and cartilage degeneration in OA model rats. Serum metabolomics revealed that the intervention effect may be closely related to arachidonic acid metabolism pathway. Network pharmacologic prediction showed that COX-2 was the key target of TFRD in treating OA, and its mechanism might be related with NFκB, apoptosis, AMPK and arachidonic acid metabolism pathway. In vivo experiments indicated that TFRD can inhibit the abnormal expression of COX-2 mRNA in OA model rats. In the in vitro studies, the expression of COX-2 mRNA and protein increased, AMPK phosphorylation was inhibited, and NFκB signaling pathway was activated in IL-1β-induced chondrocytes, and these changes can be reversed by TFRD. After the activation of AMPK signaling pathway or the block-down of NFκB signaling pathway, the effect of TFRD on COX-2 mRNA expression was significantly weakened.
TFRD can inhibit COX-2-mediated arachidonic acid metabolites, and its mechanism is closely related to AMPK/NFκB pathway, which may be a key mechanism in the treatment of OA.
既往临床研究发现骨碎补总黄酮（TFRD）对骨关节炎（OA）有良好治疗作用，但其治疗机制有待进一步研究。
采用 Hulth 法建立 OA 大鼠模型，并给予 TFRD 干预。进行病理评估以评价 TFRD 对软骨的保护作用。检测血清代谢组学和网络药理学以预测 TFRD 治疗 OA 的机制。在进一步实验中，进行分子生物学实验以在体内和体外证实预测的机制。
TFRD 可有效减少 OA 模型大鼠软骨细胞凋亡和软骨退变。血清代谢组学显示干预效果可能与花生四烯酸代谢途径密切相关。网络药理学预测表明 COX-2 是 TFRD 治疗 OA 的关键靶点，其机制可能与 NFκB、细胞凋亡、AMPK 和花生四烯酸代谢途径有关。体内实验表明 TFRD 可抑制 OA 模型大鼠 COX-2 mRNA 的异常表达。在体外研究中，IL-1β 诱导的软骨细胞中 COX-2 mRNA 和蛋白表达增加，AMPK 磷酸化受到抑制，NFκB 信号通路被激活，而这些变化可被 TFRD 逆转。激活 AMPK 信号通路或阻断 NFκB 信号通路后，TFRD 对 COX-2 mRNA 表达的作用显著减弱。
TFRD 可抑制 COX-2 介导的花生四烯酸代谢产物，其机制与 AMPK/NFκB 途径密切相关，这可能是其治疗 OA 的关键机制。
