Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
Ann Rheum Dis. 2014 Jul;73(7):1397-404. doi: 10.1136/annrheumdis-2012-202620. Epub 2013 May 30.
Important roles for SIRT1 are implicated in ageing and age-related diseases. The role of SIRT1 in osteoarthritis (OA), however, remains partially unknown. To investigate the role of SIRT1 in chondrocytes in vivo, cartilage-specific Sirt1-conditional knockout (CKO) mice were analysed using an experimental OA model.
OA was surgically induced in 8-week-old C57BL6/J (wild-type) mice and Sirt1-CKO (Sirt1(flox)/(flox); Col2a1-Cre) mice generated using the Cre-loxP system. We examined changes in Sirt1 protein during the development of surgically-induced OA and during ageing in wild-type mice. OA progression in Sirt1-CKO mice was evaluated histologically at 2, 4 and 8 weeks after surgery, and at 1 year of age without surgery compared with control (Sirt1(flox)/(flox)) mice.
The number of Sirt1-positive chondrocytes decreased during ageing, and although it was increased at 2 weeks after surgery, then gradually decreased to the presurgical level during the progression of OA in wild-type mice. Sirt1-CKO mice showed no obvious skeletal abnormalities. The histological OA score was significantly higher in 1-year-old Sirt1-CKO mice than in control mice. Sirt1-CKO mice showed accelerated OA progression at 2 and 4 (but not 8) weeks compared with control mice. Immunohistochemical analysis revealed increases in type X collagen, matrix metalloproteinase 13, a disintegrin and metalloproteinase with thrombospondin motifs-5, apoptotic markers, and acetylated nuclear factor-κB p65 in Sirt1-CKO mice compared with control mice 2 weeks after surgery.
Loss of Sirt1 in chondrocytes led to the accelerated development of OA in mice. Our observations suggest that SIRT1 has a preventive role against the development of OA.
SIRT1 在衰老和与年龄相关的疾病中起着重要作用。然而，SIRT1 在骨关节炎（OA）中的作用尚不完全清楚。为了研究 SIRT1 在软骨细胞中的体内作用，使用实验性 OA 模型分析了软骨特异性 Sirt1 条件敲除（CKO）小鼠。
使用 Cre-loxP 系统在 8 周龄 C57BL6/J（野生型）小鼠和 Sirt1-CKO（Sirt1(flox)/(flox)；Col2a1-Cre）小鼠中诱导 OA。我们检查了 Sirt1 蛋白在手术诱导的 OA 发展过程中和野生型小鼠衰老过程中的变化。在手术后 2、4 和 8 周以及未经手术的 1 年时，评估 Sirt1-CKO 小鼠的 OA 进展，并与对照（Sirt1(flox)/(flox)）小鼠进行比较。
随着年龄的增长，Sirt1 阳性软骨细胞的数量减少，尽管在手术后 2 周增加，但在野生型小鼠 OA 进展过程中逐渐减少至术前水平。Sirt1-CKO 小鼠没有明显的骨骼异常。与对照小鼠相比，1 岁的 Sirt1-CKO 小鼠的组织学 OA 评分显着更高。与对照小鼠相比，Sirt1-CKO 小鼠在手术后 2 和 4（但不是 8）周时 OA 进展更快。免疫组织化学分析显示，与对照小鼠相比，Sirt1-CKO 小鼠在手术后 2 周时，I 型胶原、基质金属蛋白酶 13、去整合素和金属蛋白酶与血栓反应蛋白-5、凋亡标志物和乙酰化核因子-κB p65 的表达增加。
软骨细胞中 Sirt1 的缺失导致小鼠 OA 的快速发展。我们的观察结果表明，SIRT1 对 OA 的发展具有预防作用。
