Uncoupled extracellular matrix (ECM) causes cartilage degeneration and osteoarthritis (OA) by suppressing the synthesis and activating the degradation of ECM components. Gingko biloba is a natural Chinese herb with a variety of biological functions; however, the extent to which it can protect against OA and the mechanisms involved are unknown. In our study, using bioinformatics tools, we were able to identify an important lactone, bilobalide (BB), from Gingko biloba. In vitro experiments were performed to evaluate the potential therapeutic effects of BB on ECM homeostasis. In vivo experiments were conducted to assess the protection of systemic administration of BB on cartilage degeneration. Molecular mechanisms underlying BB-regulated anti-arthritic role were further explored. In interleukin-1β-incubated human chondrocytes, in vitro treatment with BB increased the expression of cartilage anabolic proteins, while inhibiting the activities of ECM degrading enzymes. In a mice model, systemic administration of BB, in vivo, prevented post-traumatic cartilage erosion and attenuated the formation of abnormal osteophytes in the subchondral bone. Mechanistically, the activation of the adenosine 5′-monophosphate-activated protein kinase (AMPK)-sirtuin 1 (SIRT1) signaling pathway was involved in the anti-arthritic effects of BB. In vitro, blocking BB’s chondroprotection with the AMPK-specific inhibitor Compound C abrogated it. These results demonstrated that BB extracted from Gingko biloba regulates ECM balance to prevent OA by activating the AMPK-SIRT1 signaling pathway. This study proposed the monomer BB, a traditional Chinese medicine, as a de novo therapeutic insight for OA. Schematic representation of the experimental design. Based on the bioinformatic analysis, bilobalide (BB), a natural herb Gingko biloba-derived ingredient, was identified as a candidate for treating osteoarthritis. In vitro, BB treatment not only facilitates cartilage extracellular matrix synthesis but also inhibits proteolytic enzyme activities. In vivo intraperitoneal injection of BB improves cartilage degeneration and subchondral bone sclerosis. BB, in particular, had anti-arthritic effects by activating the AMPK-SIRT1 signaling pathway.

中文翻译：

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银杏叶内酯通过激活 AMPK-SIRT1 信号通路预防骨关节炎

解偶联的细胞外基质 (ECM) 通过抑制 ECM 成分的合成和激活降解导致软骨退化和骨关节炎 (OA)。银杏是一种具有多种生物学功能的天然中草药；但是，它可以在多大程度上防止 OA 以及所涉及的机制尚不清楚。在我们的研究中，使用生物信息学工具，我们能够从银杏中鉴定出一种重要的内酯，即白果内酯 (BB)。进行体外实验以评估 BB 对 ECM 稳态的潜在治疗作用。进行体内实验以评估全身施用BB对软骨退化的保护作用。进一步探讨了 BB 调节的抗关节炎作用的分子机制。在白细胞介素 1β 孵育的人软骨细胞中，BB体外处理增加了软骨合成代谢蛋白的表达，同时抑制了ECM降解酶的活性。在小鼠模型中，体内全身施用 BB 可防止创伤后软骨侵蚀并减轻软骨下骨中异常骨赘的形成。从机制上讲，5'-一磷酸腺苷活化蛋白激酶 (AMPK)-sirtuin 1 (SIRT1) 信号通路的激活参与了 BB 的抗关节炎作用。在体外，用 AMPK 特异性抑制剂化合物 C 阻断 BB 的软骨保护作用消除了它。这些结果表明，从银杏叶中提取的 BB 通过激活 AMPK-SIRT1 信号通路来调节 ECM 平衡以预防 OA。本研究提出单体BB，一种中药，作为 OA 的从头治疗见解。实验设计的示意图。基于生物信息学分析，银杏叶衍生的天然草本植物白果内酯 (BB) 被确定为治疗骨关节炎的候选药物。在体外，BB 治疗不仅促进软骨细胞外基质合成，而且抑制蛋白水解酶活性。体内腹腔注射 BB 可改善软骨退化和软骨下骨硬化。特别是 BB，通过激活 AMPK-SIRT1 信号通路具有抗关节炎作用。BB 治疗不仅促进软骨细胞外基质合成，而且抑制蛋白水解酶活性。体内腹腔注射 BB 可改善软骨退化和软骨下骨硬化。特别是 BB，通过激活 AMPK-SIRT1 信号通路具有抗关节炎作用。BB 治疗不仅促进软骨细胞外基质合成，而且抑制蛋白水解酶活性。体内腹腔注射 BB 可改善软骨退化和软骨下骨硬化。特别是 BB，通过激活 AMPK-SIRT1 信号通路具有抗关节炎作用。