Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice

Bone & Joint Research

article

K. Nishida¹  T. Matsushita¹  K. Takayama¹  T. Tanaka¹  N. Miyaji¹  K. Ibaraki¹  D. Araki¹  N. Kanzaki¹  T. Matsumoto¹  R. Kuroda¹ 

[1] Kobe University

关键词: SIRT1;    SRT1720;    Osteoarthritis;    Synovitis;   

DOI  :  10.1302/2046-3758.73.BJR-2017-0227.R1

学科分类：骨科学

来源: British Editorial Society Of Bone And Joint Surgery

【 摘 要 】

ObjectivesThis study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model.MethodsOsteoarthritis was surgically induced by destabilization of the medial meniscus in eightweek-old C57BL/6 male mice. SRT1720 was administered intraperitoneally twice a weekafter surgery. Osteoarthritis progression was evaluated histologically using the Osteoarthritis Research Society International (OARSI) score at four, eight, 12 and 16 weeks. The expression of SIRT1, matrix metalloproteinase 13 (MMP-13), a disintegrin and metalloproteinasewith thrombospondin motifs-5 (ADAMTS-5), cleaved caspase-3, PARP p85, and acetylatednuclear factor (NF)-κB p65 in cartilage was examined by immunohistochemistry. Synovitis was also evaluated histologically. Primary mouse epiphyseal chondrocytes were treatedwith SRT1720 in the presence or absence of interleukin 1 beta (IL-1β), and gene expressionchanges were examined by real-time polymerase chain reaction (PCR).ResultsThe OARSI score was significantly lower in mice treated with SRT1720 than in control miceat eight and 12 weeks associated with the decreased size of osteophytes at four and eightweeks. The delayed OA progression in the mice treated with SRT1720 was also associatedwith increased SIRT1-positive chondrocytes and decreased MMP-13-, ADAMTS-5-, cleavedcaspase-3-, PARP p85-, and acetylated NF-κB p65-positive chondrocytes and decreased synovitis at four and eight weeks. SRT1720 treatment partially rescued the decreases in collagentype II alpha 1 (COL2A1) and aggrecan caused by IL-1β, while also reducing the induction ofMMP-13 by IL-1β in vitro.ConclusionThe intraperitoneal injection of SRT1720 attenuated experimental OA progression in mice,indicating that SRT1720 could be a new therapeutic approach for OA.

【 授权许可】

CC BY-NC