OBJECTIVE Previous findings suggest that silent information regulator 2 ortholog 1 (SIRT1) plays essential roles in chondrocytes and prevents osteoarthritis (OA) development. The purpose of this study was to investigate the effects of intraperitoneal (i.p.) and intra-articular (i.a.) administration of the SIRT1 activator SRT2104, which has been approved for use in humans. DESIGN OA was induced by destabilizing the medial meniscus in the knee joint of 12-week-old CL57BL/6J mice. The mice were divided into 3 groups, that is, the control group, SRT2104 i.p.-injection group, and SRT2104 i.a.-injection group. Tissues were harvested at 4, 8, 12, and 16 weeks postsurgery. OA progression was evaluated using the Osteoarthritis Research Society International (OARSI) score. The production of OA-related proteins in cartilage and synovium was examined by immunohistochemistry. RESULTS OARSI scores in the control group were significantly higher at 8 and 12 weeks compared with other 2 groups. Immunohistochemical analysis showed that Sirt1 and type-2 collagen significantly increased, whereas MMP-13, ADAMTS-5, IL-1β, IL-6, cleaved caspase 3, PARP p85, acetylated NF-κB p65, and iNOS decreased significantly in cartilage tissues from the i.p. and i.a, SRT2104 groups. In the synovium, more iNOS-positive M1-like macrophages were observed in the control group than in the i.p. and i.a, SRT2104 groups, whereas more CD206-positive M2-like macrophages were detected in the i.p. and i.a. SRT2104 groups. CONCLUSIONS Both i.p. and i.a. SRT2104 injection reduced OA progression in the mouse OA model, suggesting that SRT2104 can serve as a new treatment for OA.

中文翻译：

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通过施用 SRT2014（沉默信息调节器 2 Ortholog 1 的激活剂）抑制小鼠膝骨关节炎进展。

目的 先前的研究结果表明，沉默信息调节因子 2 直向同源物 1 (SIRT1) 在软骨细胞中发挥重要作用并防止骨关节炎 (OA) 的发展。本研究的目的是研究已获准用于人类的 SIRT1 激活剂 SRT2104 的腹膜内 (ip) 和关节内 (ia) 给药效果。DESIGN OA 是通过破坏 12 周龄 CL57BL/6J 小鼠膝关节内侧半月板的稳定性而诱导的。将小鼠分为3组，即对照组、SRT2104 ip-注射组和SRT2104 ia-注射组。在术后 4、8、12 和 16 周收获组织。使用国际骨关节炎研究协会 (OARSI) 评分评估 OA 进展。通过免疫组织化学检查软骨和滑膜中 OA 相关蛋白的产生。结果对照组的OARSI评分在第8周和第12周时明显高于其他2组。免疫组织化学分析显示，Sirt1 和 2 型胶原蛋白显着增加，而 MMP-13、ADAMTS-5、IL-1β、IL-6、cleaved caspase 3、PARP p85、乙酰化 NF-κB p65 和 iNOS 在软骨组织中显着降低来自 ip 和 ia，SRT2104 组。在滑膜中，对照组比ip和ia、SRT2104组观察到更多的iNOS阳性M1样巨噬细胞，而在ip和ia SRT2104组中检测到更多的CD206阳性M2样巨噬细胞。结论 ip 和 ia SRT2104 注射均减少了小鼠 OA 模型中的 OA 进展，