Department of Orthopedic Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan.
Cartilage. 2021 Dec;13(2_suppl):1356S-1366S. doi: 10.1177/1947603519900795. Epub 2020 Jan 28.
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.
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.
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.
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.
先前的研究结果表明，沉默信息调节因子 2 同源物 1（SIRT1）在软骨细胞中发挥重要作用，并可预防骨关节炎（OA）的发展。本研究旨在探讨已被批准用于人类的 SIRT1 激活剂 SRT2104 的腹腔内（i.p.）和关节内（i.a.）给药的效果。
通过破坏膝关节内侧半月板，在 12 周龄 CL57BL/6J 小鼠中诱导 OA。将小鼠分为对照组、SRT2104 i.p.注射组和 SRT2104 i.a.注射组。术后 4、8、12 和 16 周采集组织。采用骨关节炎研究协会国际（OARSI）评分评估 OA 进展情况。通过免疫组织化学法检测软骨和滑膜中 OA 相关蛋白的产生。
与其他两组相比，对照组在 8 周和 12 周时 OARSI 评分明显更高。免疫组织化学分析显示，Sirt1 和型 2 胶原显著增加，而 MMP-13、ADAMTS-5、IL-1β、IL-6、cleaved caspase 3、PARP p85、乙酰化 NF-κB p65 和 iNOS 在 i.p.和 i.a 组的软骨组织中显著减少。在滑膜中，与 i.p.和 i.a.组相比，对照组中更多的 iNOS 阳性 M1 样巨噬细胞，而 i.p.和 i.a.组中检测到更多的 CD206 阳性 M2 样巨噬细胞。
腹腔内和关节内注射 SRT2104 均可减轻小鼠 OA 模型中的 OA 进展，表明 SRT2104 可作为 OA 的一种新治疗方法。
