Overexpression of Sirtuin 6 suppresses cellular senescence and NF-κB mediated inflammatory responses in osteoarthritis development.
Overexpression of Sirtuin 6 suppresses cellular senescence and NF-κB mediated inflammatory responses in osteoarthritis development.
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Sirtuin 6 的过度表达抑制骨关节炎发展中的细胞衰老和 NF-κB 介导的炎症反应
DOI：
10.1038/srep17602
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发表时间：
2015-12-07
影响因子：
4.6
通讯作者：
Pan Z
中科院分区：
文献类型：
--
作者：
Wu Y;Chen L;Wang Y;Li W;Lin Y;Yu D;Zhang L;Li F;Pan Z
我们研究的目的是评估Sirt6，一种NAD +依赖性组蛋白去乙酰化酶，是否通过抑制细胞衰老和炎症反应在软骨变性中发挥保护作用。采用免疫荧光法和western blot法比较sirt6在正常和OA人膝关节软骨组织中的表达水平。观察sirt6过表达对软骨细胞增殖性衰老及NF-κB靶基因表达的影响。对OA小鼠膝关节进行组织学评估，以评估sirt6过表达对小鼠软骨细胞的体内影响。我们发现，与正常人相比，OA患者关节软骨细胞中的sirt6水平明显降低。SA-β-gal染色显示sirt6过表达抑制了软骨细胞的复制性衰老。同时，过表达sirt6显著降低NF-κB依赖基因的表达。对OA小鼠膝关节软骨进行红花素- o染色和OARSI评分显示，关节内注射lentii - sirt6对小鼠软骨细胞有保护作用。这些数据强烈表明Sirt6的过表达可以通过减少炎症反应和软骨细胞衰老来阻止OA的发展。因此，Sirt6特异性激活剂的开发可能具有治疗OA的潜力。
The aim of our study was to evaluate if Sirt6, a NAD + dependent histone deacetylase, plays a protective role in cartilage degeneration by suppressing cellular senescence and inflammatory responses. The expression level of sirt6 in normal and OA human knee articular cartilage was compared by immunofluorescence and western blotting. The effect of sirt6 overexpression on replicative senescence of chondrocytes and NF-κB target genes expression was evaluated. Histological assessment of OA mice knee joint was carried out to assess thein vivoeffects of sirt6 overexpression on mice chondrocytes. We found sirt6 level was significantly decreased in the articular chondrocytes of OA patients compare to normal human. SA-β-gal staining revealed that overexpression of sirt6 suppressed replicative senescence of chondrocytes. Meanwhile, the expression of NF-κB dependent genes were significantly attenuated by sirt6 overxpression. Safranin-O staining and OARSI score of knee joint cartilage in OA mice revealed that Lenti-Sirt6 intraarticular injection could protect mice chondrocytes from degeneration. These data strongly suggest that overexpression of Sirt6 can prevent OA development by reducing both the inflammatory response and chondrocytes senescence. Therefore, the development of specific activators of Sirt6 may have therapeutic potential for the treatment of OA.