N. Miyaji (Kobe, JP)
Kobe University Graduate School of Medicine Orthopaedic SurgeryPresenter Of 1 Presentation
12.2.1 - Attenuation of the knee osteoarthritis progression by administration of SIRT1 activator SRT2104 in mice
Abstract
Purpose
SIRT1 has been suggested to play protective roles against osteoarthritis (OA) progression. The purpose of this study was to investigate the effects of intraperitoneal and intra-articular administration of SIRT1 activator SRT2104, which can be used in human, on OA progression.
Methods and Materials
OA was induced by destabilization of the medial meniscus in the knee joints of 12-week-old CL57BL/6J mice. Mice were divided into 3 groups; Control group (10% DMSO in isotonic saline, i.p.). SRT2104 intraperitoneal injection group (SRTi.p.; 25 mg/kg). SRT2104 intra-articular injection group (SRTi.a.; 17 ng/kg). Tissues were harvested at 4, 8, 12 and 16 weeks after surgery. OA progression was evaluated using the Osteoarthritis Research Society International (OARSI) score. The production of SIRT1, type 2 collagen, MMP-13, ADAMTS-5, cleaved caspase 3, PARP p85, acetylated NF-kB p65, IL-1b and IL-6 were examined by immunohistochemistry. For in vitro experiments, mouse primary epiphyseal chondrocytes were cultured with or without 10 ng/ml IL-1b for 24h, and then treated with or without 2.0 µM SRT2104. The expression of Sirt1, Col2a1, Mmp-3, Mmp-13 and Adamts-5 were examined by Real-time PCR.
Results
The OARSI score was significantly lower in the SRTi.p. group and the SRTi.a. group compared with that in the control group at 8 and 12 weeks, while there was no statistically significant difference between the SRTi.p. group and SRTi.a. group (Figure 1). The immunohistochemical analysis showed that Sirt1 and type 2 collagen were significantly more detected while MMP-13, ADAMTS-5, cleaved caspase 3, PARP p85, acetylated NF-kB p65, IL-1b and IL-6 were significantly decreased in the SRTi.p. and SRTi.a. groups compared with the control group (Figure 2). The treatment with SRT2104 significantly increased the expression of Sirt1 and Col2a1 while decreased Mmp3 and Mmp13.
Conclusion
Both intraperitoneal and intra-articular injection of SRT2104 attenuated OA progression in the mouse OA model. SRT2104 could be a new treatment for OA.