Department of Sports Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Sports Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Sports Medicine and Joint Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Phytomedicine. 2024 Dec;135:156052. doi: 10.1016/j.phymed.2024.156052. Epub 2024 Oct 2.
Chondrocyte senescence and inflammation are hallmarks of osteoarthritis (OA). Forsythiaside A (FTA), a phenylethanol glycoside isolated from air-dried fruits of Forsythia, has been reported to have significant anti-inflammatory and antioxidant properties. However, its protective effects against OA have not been elucidated.
We explored the therapeutic efficacy of FTA in inhibiting chondrocyte senescence and inflammation during OA, as well as the potential underlying mechanisms.
This study aimed to investigate the novel mechanism of FTA in alleviating OA in both cell and animal models.
The protective effect of FTA against tert‑butyl hydroperoxide-induced chondrocyte damage was assessed, and the effects of FTA on cartilage aging and OA progression were evaluated using a medial meniscus (DMM)-induced knee OA mouse model. The regulatory effects of FTA on the NLRP3 Inflammasome, mitophagy, and the PKC/Nrf2 pathway were also explored.
In vitro, FTA improved mitochondrial function, enhanced mitophagy, suppressed NLRP3 inflammasome activation, and inhibited chondrocyte senescence; however, these chondroprotective effects were partially reversed after mitophagy inhibition, NLRP3 inflammasome activation, and Nrf2 pathway inhibition. Furthermore, we found that FTA directly interacts with Nrf2 and enhances its phosphorylation by protein kinase C (PKC). In vivo, FTA attenuated the pathological signs of knee OA in a DMM-model mouse model, which was partially reversed by ML385.
FTA inhibited chondrocyte senescence and OA progression by activating the PKC-Nrf2 pathway. Thus, FTA is a potential novel therapeutic agent for OA.
软骨细胞衰老和炎症是骨关节炎（OA）的特征。从干燥的连翘果实中分离得到的苯乙醇糖苷连翘脂素 A（FTA）已被报道具有显著的抗炎和抗氧化作用。然而，其对 OA 的保护作用尚未阐明。
我们探讨了 FTA 抑制 OA 中软骨细胞衰老和炎症的治疗效果，以及潜在的作用机制。
本研究旨在探讨 FTA 在细胞和动物模型中缓解 OA 的新机制。
评估 FTA 对叔丁基过氧化氢诱导的软骨细胞损伤的保护作用，并用内侧半月板（DMM）诱导的膝骨关节炎小鼠模型评估 FTA 对软骨老化和 OA 进展的影响。还探讨了 FTA 对 NLRP3 炎性体、线粒体自噬和 PKC/Nrf2 通路的调节作用。
在体外，FTA 改善了线粒体功能，增强了线粒体自噬，抑制了 NLRP3 炎性体的激活，抑制了软骨细胞衰老；然而，在抑制线粒体自噬、NLRP3 炎性体激活和 Nrf2 通路抑制后，这些软骨保护作用部分逆转。此外，我们发现 FTA 直接与 Nrf2 相互作用，并通过蛋白激酶 C（PKC）增强其磷酸化。在体内，FTA 减轻了 DMM 模型小鼠膝骨关节炎的病理征象，而 ML385 部分逆转了这一作用。
FTA 通过激活 PKC-Nrf2 通路抑制软骨细胞衰老和 OA 进展。因此，FTA 是一种治疗 OA 的潜在新型治疗药物。
