Nishida K, Matsushita T, Takayama K, Tanaka T, Miyaji N, Ibaraki K, Araki D, Kanzaki N, Matsumoto T, Kuroda R
Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho Chuo-ku, Kobe, Hyogo 6500017, Japan.
Bone Joint Res. 2018 May 5;7(3):252-262. doi: 10.1302/2046-3758.73.BJR-2017-0227.R1. eCollection 2018 Mar.
This study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model.
Osteoarthritis was surgically induced by destabilization of the medial meniscus in eight-week-old C57BL/6 male mice. SRT1720 was administered intraperitoneally twice a week after 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 metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), cleaved caspase-3, PARP p85, and acetylated nuclear factor (NF)-κB p65 in cartilage was examined by immunohistochemistry. Synovitis was also evaluated histologically. Primary mouse epiphyseal chondrocytes were treated with SRT1720 in the presence or absence of interleukin 1 beta (IL-1β), and gene expression changes were examined by real-time polymerase chain reaction (PCR).
The OARSI score was significantly lower in mice treated with SRT1720 than in control mice at eight and 12 weeks associated with the decreased size of osteophytes at four and eight weeks. The delayed OA progression in the mice treated with SRT1720 was also associated with increased SIRT1-positive chondrocytes and decreased MMP-13-, ADAMTS-5-, cleaved caspase-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 collagen type II alpha 1 (COL2A1) and aggrecan caused by IL-1β, while also reducing the induction of MMP-13 by IL-1β .
The intraperitoneal injection of SRT1720 attenuated experimental OA progression in mice, indicating that SRT1720 could be a new therapeutic approach for OA.Cite this article: K. Nishida, T. Matsushita, K. Takayama, T. Tanaka, N. Miyaji, K. Ibaraki, D. Araki, N. Kanzaki, T. Matsumoto, R. Kuroda. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. 2018;7:252-262. DOI: 10.1302/2046-3758.73.BJR-2017-0227.R1.
本研究旨在使用实验性骨关节炎（OA）模型，研究强效SIRT1激活剂SRT1720对OA进展的影响。
通过破坏8周龄C57BL/6雄性小鼠的内侧半月板手术诱导骨关节炎。术后每周两次腹腔注射SRT1720。在4、8、12和16周时，使用国际骨关节炎研究学会（OARSI）评分对OA进展进行组织学评估。通过免疫组织化学检查软骨中SIRT1、基质金属蛋白酶13（MMP-13）、含血小板反应蛋白基序的解聚素和金属蛋白酶-5（ADAMTS-5）、裂解的半胱天冬酶-3、PARP p85和乙酰化核因子（NF）-κB p65的表达。滑膜炎也进行了组织学评估。在有或无白细胞介素1β（IL-1β）的情况下用SRT1720处理原代小鼠骨骺软骨细胞，并通过实时聚合酶链反应（PCR）检查基因表达变化。
在8周和12周时，用SRT1720处理的小鼠的OARSI评分显著低于对照小鼠，这与4周和8周时骨赘大小的减小有关。用SRT1720处理的小鼠中OA进展的延迟也与SIRT1阳性软骨细胞增加以及MMP-13、ADAMTS-5、裂解的半胱天冬酶-3、PARP p85和乙酰化NF-κB p65阳性软骨细胞减少以及4周和8周时滑膜炎减少有关。SRT1720处理部分挽救了由IL-1β引起的II型胶原α1（COL2A1）和聚集蛋白聚糖的减少，同时也减少了IL-1β对MMP-13的诱导。
腹腔注射SRT1720可减轻小鼠实验性OA的进展，表明SRT1720可能是OA的一种新的治疗方法。引用本文：K. Nishida，T. Matsushita，K. Takayama，T. Tanaka，N. Miyaji，K. Ibaraki，D. Araki，N. Kanzaki，T. Matsumoto，R. Kuroda。腹腔注射SIRT1激活剂SRT1720可减轻小鼠实验性骨关节炎的进展。2018；7：252 - 262。DOI：10.1302/2046 - 3758.73.BJR - 2017 - 0227.R1。
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