The Second Clinical College, Zhejiang Chinese Medical University, Hangzhou, China.
The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
J Cell Mol Med. 2024 Aug;28(16):e70019. doi: 10.1111/jcmm.70019.
Knee osteoarthritis (KOA) is a chronic joint disease that significantly affects the health of the elderly. As an herbal remedy, Gubi decoction (GBD) has been traditionally used for the treatment of osteoarthritis-related syndromes. However, the anti-KOA efficacy and mechanism of GBD remain unclear. This study aimed to experimentally investigate the anti-KOA efficacy and the underlying mechanism of GBD. The medial meniscus (DMM) mice model and IL-1β-stimulated chondrocytes were, respectively, constructed as in vivo and in vitro models of KOA to evaluate the osteoprotective effect and molecular mechanism of GBD. The UPLC-MS/MS analysis showed that GBD mainly contained pinoresinol diglucoside, rehmannioside D, hesperidin, liquiritin, baohuoside I, glycyrrhizic acid, kaempferol and tangeretin. Animal experiment showed that GBD could alleviate articular cartilage destruction and recover histopathological alterations in DMM mice. In addition, GBD inhibited chondrocyte apoptosis and restored DMM-induced dysregulated autophagy evidenced by the upregulation of ATG7 and LC3 II/LC3 I but decreased P62 level. Mechanistically, METTL3-mediated mA modification decreased the expression of ATG7 in DMM mice, as it could be significantly attenuated by GBD. METTL3 overexpression significantly counteracted the protective effect of GBD on chondrocyte autophagy. Further research showed that GBD promoted proteasome-mediated ubiquitination degradation of METLL3. Our findings suggest that GBD could act as a protective agent against KOA. The protective effect of GBD may result from its promotion on chondrocyte autophagy by suppressing METTL3-dependent ATG7 mA methylation.
膝骨关节炎（KOA）是一种慢性关节疾病，严重影响老年人的健康。骨痹汤（GBD）作为一种草药疗法，传统上用于治疗与骨关节炎相关的综合征。然而，GBD 治疗 KOA 的疗效和机制尚不清楚。本研究旨在实验研究 GBD 治疗 KOA 的疗效和作用机制。内侧半月板（DMM）小鼠模型和 IL-1β刺激的软骨细胞分别作为 KOA 的体内和体外模型，以评估 GBD 的护骨作用和分子机制。UPLC-MS/MS 分析表明，GBD 主要含有松脂醇二葡萄糖苷、地黄苷 D、橙皮苷、甘草苷、宝藿苷 I、甘草酸、山奈酚和橙皮素。动物实验表明，GBD 可减轻关节软骨破坏，并恢复 DMM 小鼠的组织病理学改变。此外，GBD 抑制软骨细胞凋亡，并恢复 DMM 诱导的自噬失调，表现为 ATG7 和 LC3 II/LC3 I 的上调，但降低 P62 水平。机制上，METTL3 介导的 mA 修饰降低了 DMM 小鼠中 ATG7 的表达，而 GBD 可显著减弱其表达。METTL3 过表达显著抵消了 GBD 对软骨细胞自噬的保护作用。进一步的研究表明，GBD 促进蛋白酶体介导的 METTL3 泛素化降解。我们的研究结果表明，GBD 可作为 KOA 的保护剂。GBD 的保护作用可能是通过抑制 METTL3 依赖性 ATG7 mA 甲基化来促进软骨细胞自噬。
