LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes
LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes
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DOI：
10.1096/fj.201601253r
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发表时间：
2017-07-01
期刊：
影响因子：
4.8
通讯作者：
Dvir-Ginzberg, Mona
中科院分区：
文献类型：
--
作者：
Elayyan, Jinan;Lee, Eun-Jin;Dvir-Ginzberg, Mona
骨关节炎 (OA) 期间 SIRT1 活性和水平降低会导致软骨逐渐丧失。软骨基质的损失伴随着基质金属蛋白酶 (MMP) 13 的增加，部分原因是 LEF1 转录活性增强。在这项研究中，我们评估了 SIRT1 在 LEF1 介导的人 OA 软骨细胞中 MMP13 基因表达中的作用。结果表明，SIRT1 过表达或白藜芦醇激活期间，MMP13 蛋白水平和酶活性显着降低。相反，在用 SIRT1 siRNA 转染或用烟酰胺 (NAM)（一种 Sirtuin 抑制剂）处理的软骨细胞中，MMP13 基因表达降低。软骨细胞受到 IL-113（一种参与 OA 发病机制的细胞因子）攻击后，LEF1 蛋白水平和基因表达增强，导致 MMP13 基因表达增加；然而，IL-113 攻击期间 SIRT1 的过度表达阻碍了 LEF1 水平和 MMP13 基因表达。之前的报道表明，LEF1 与 MMP13 启动子结合并反式激活其表达，但我们观察到 SIRT1 抑制 LEF1 蛋白和 mRNA 表达，最终降低 LEF1 转录活性（通过荧光素酶测定判断）。最后，来自 Sirt1-/ 的小鼠关节软骨呈现出增加的 LEF1 和 MMP13 蛋白水平，类似于人类 OA 软骨。因此，首次证明 SIRT1 抑制人 OA 软骨细胞中的 MMP13，这似乎至少部分是通过抑制转录因子 LEF1（一种已知的 MMP13 基因表达调节剂）来介导的。 Elayyan, J.、Lee, E.-J.、Gabay, O.、Smith, C. A.、Qiq, O.、Reich, E.、Mobasheri, A.、Henrotin, Y.、Kimber, S. J.、Dvir-Ginzberg, M. LEF1 介导的 MMP13 基因表达在人软骨细胞中被 SIRT1 抑制。
Reduced SIRT1 activity and levels during osteoarthritis (OA) promote gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase in matrix metalloproteinase (MMP) 13, partially because of enhanced LEF1 transcriptional activity. In this study, we assessed the role of SIRT1 in LEF1-mediated MMP13 gene expression in human OA chondrocytes. Results showed that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-113, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression; however, overexpression of SIRT1 during IL-113 challenge impeded LEF1 levels and MMP13 gene expression. Previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, but we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mouse articular cartilage from Sirt1-/presented increased LEF1 and MMP13 protein levels, similar to human OA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in human OA chondrocytes, which appears to be mediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression. Elayyan, J., Lee, E.-J., Gabay, O., Smith, C. A., Qiq, O., Reich, E., Mobasheri, A., Henrotin, Y., Kimber, S. J., Dvir-Ginzberg, M. LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes.