Hoshi Hiroko, Akagi Ryuichiro, Yamaguchi Satoshi, Muramatsu Yuta, Akatsu Yorikazu, Yamamoto Yohei, Sasaki Toshihide, Takahashi Kazuhisa, Sasho Takahisa
Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
Center for Preventive Medicine, Chiba University, Chiba, Japan.
Cell Tissue Res. 2017 May;368(2):379-387. doi: 10.1007/s00441-016-2563-y. Epub 2017 Jan 24.
Matrix metalloproteinase 13 (MMP13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) are thought to play critical roles in cartilage degradation at the early phase of osteoarthritis (OA). The aim of this study is to examine the effect of chemically modified Mmp13 or Adamts5 small interfering RNA (siRNA), alone or in combination, in a mouse OA model. OA pathology was surgically induced in 9-week-old male C57/BL6 mice (n = 64) via destabilization of the medial meniscus (DMM). We used chemically modified siRNA (Accell siRNAs®) for Mmp13 and Adamts5, as well as a non-targeting control and evaluated their combined and individual effects after injection in the DMM model. The control group (n = 16) was injected with non-targeting siRNA and the normal group (n = 16) did not undergo any surgical induction or intra-articular injection. Histological assessment of the articular cartilage was conducted at 4 and 8 weeks post-DMM surgery to evaluate OA progression. Significant improvement in the histological score was observed at 8 weeks after DMM in all three siRNA-treated groups compared to the control siRNA-injected group. The score of the combined group was significantly lower than that of the Adamts5 siRNA-only group. No significant differences were noted between the Mmp13 siRNA-only group and the combined group. Combined intra-articular injection of Mmp13 and Adamts5 siRNA resulted in almost the same inhibitory effects as Mmp13 siRNA alone on cartilage degradation at the early phase of OA.
基质金属蛋白酶13（MMP13）和含血小板反应蛋白基序的解聚素和金属蛋白酶5（ADAMTS5）被认为在骨关节炎（OA）早期阶段的软骨降解中起关键作用。本研究的目的是在小鼠OA模型中检测化学修饰的Mmp13或Adamts5小干扰RNA（siRNA）单独或联合使用的效果。通过内侧半月板失稳（DMM）手术诱导9周龄雄性C57/BL6小鼠（n = 64）发生OA病理改变。我们使用针对Mmp13和Adamts5的化学修饰siRNA（Accell siRNAs®）以及非靶向对照，并在DMM模型中注射后评估它们的联合和单独作用。对照组（n = 16）注射非靶向siRNA，正常组（n = 16）未接受任何手术诱导或关节内注射。在DMM手术后4周和8周对关节软骨进行组织学评估，以评估OA进展。与注射对照siRNA的组相比，所有三个siRNA治疗组在DMM后8周时组织学评分均有显著改善。联合组的评分显著低于仅注射Adamts5 siRNA的组。仅注射Mmp13 siRNA的组与联合组之间未观察到显著差异。关节内联合注射Mmp13和Adamts5 siRNA在OA早期对软骨降解的抑制作用与单独注射Mmp13 siRNA几乎相同。
