SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin-like growth factor receptor pathway.
SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin-like growth factor receptor pathway.
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DOI：
10.1002/art.27369
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发表时间：
2010-05
影响因子：
--
通讯作者：
Hall, David J.
中科院分区：
文献类型：
--
作者：
Gagarina, Viktoria;Gabay, Odile;Dvir-Ginzberg, Mona;Lee, Eun Jin;Brady, Jillian K.;Quon, Michael J.;Hall, David J.
蛋白去乙酰酶SirT1通过不同的机制抑制多种细胞系统中的细胞凋亡，但其在软骨细胞死亡中的作用尚不清楚。在这里，我们评估了SirT1在骨关节炎人软骨细胞存活中的作用。将SIRT1、PTP1B、PTP1B突变型表达载体及SirT1siRNA、PTP1BsiRNA分别导入原代人软骨细胞。用流式细胞仪检测细胞凋亡率，免疫印迹法检测IGFR/Akt信号通路的激活情况。对骨性关节炎(OA)和正常膝关节软骨标本进行免疫组织化学染色。在有或无肿瘤坏死因子α/放线菌素D作用下，SirT1在软骨细胞中的表达均可增加软骨细胞的存活率，而siRNA降低SirT1可导致软骨细胞的凋亡率增加。SirT1在软骨细胞中的表达导致IGF受体(IGFR)及其下游的PI3K、PDK1、mTOR和Akt的激活，进而导致MDM2的磷酸化、P53的抑制和细胞凋亡的阻断。IGFR的激活至少部分是通过SirT1介导的对蛋白酪氨酸磷酸酶PTP1B的抑制来实现的。PTP1B在软骨细胞中的表达增加了细胞的凋亡率，降低了IGFR的磷酸化，而siRNA下调了PTP1B的表达，显著减少了细胞的凋亡率。来自正常供者和骨关节炎患者的软骨检查显示，PTP1B在SirT1水平降低的OA软骨中水平升高。这是第一次证明SirT1是通过下调PTP1B来调节人类软骨细胞的存活，PTP1B是一种在骨关节炎软骨中升高的有效的软骨细胞促凋亡蛋白。
The protein deacetylase SirT1 inhibits apoptosis in a variety of cell systems by distinct mechanisms, yet its role in chondrocyte death has not been explored. Here we assess the role of SirT1 in the survival of osteoarthritic human chondrocytes. SirT1, PTP1B, PTP1Bmutant expression plasmids and SirT1siRNA and PTP1BsiRNA were transfected into primary human chondrocytes. Levels of apoptosis were determined by flow cytometry and activation of components of the IGFR/Akt pathway was assessed by immunoblotting. Immunohistochemistry was performed on osteoarthritic (OA) and normal knee cartilage samples. Expression of SirT1 in chondrocytes led to increased chondrocyte survival in either the presence or absence of TNFα/Actinomycin D, while a reduction of SirT1 by siRNA led to increased in chondrocyte apoptosis. Expression of SirT1 in chondrocytes led to activation of the IGF receptor (IGFR) and the downstream kinases PI3K, PDK1, mTOR and Akt which in turn led to phosphorylation of MDM2, inhibition of p53 and a block to apoptosis. Activation of the IGFR occurs at least in part via SirT1-mediated repression of the protein tyrosine phosphatase PTP1B. Expression of PTP1B in chondrocytes increased apoptosis and reduced IGFR phosphorylation, while downregulation of PTP1B by siRNA significantly decreased apoptosis. Examination of cartilage from normal donors and osteoarthritic patients revealed that PTP1B levels are elevated in OA cartilage where SirT1 levels are decreased. This is the first demonstration that SirT1 is a mediator of human chondrocyte survival via downregulation of PTP1B a potent chondrocyte proapoptotic protein that is elevated in OA cartilage.
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影响因子：
5.3
作者：
Limesand, Kirsten H.;Schwertfeger, Kathryn L.;Anderson, Steven M.
通讯作者：
Anderson, Steven M.
影响因子：
16
作者：
Cohen, HY;Lavu, S;Sinclair, DA
通讯作者：
Sinclair, DA
影响因子：
5.3
作者：
Lemieux, ME;Yang, X;McBurney, MW
通讯作者：
McBurney, MW
影响因子：
4.8
作者：
Chen, H;Wertheimer, SJ;Quon, MJ
通讯作者：
Quon, MJ
DOI：
10.1073/pnas.0400593101
发表时间：
2004-07-06
影响因子：
11.1
作者：
Daitoku, H;Hatta, M;Fukamizu, A
通讯作者：
Fukamizu, A