PEP-1-SIRT2 causes dedifferentiation and COX-2 expression via the MAPK pathways in rabbit articular chondrocytes
PEP-1-SIRT2 causes dedifferentiation and COX-2 expression via the MAPK pathways in rabbit articular chondrocytes
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DOI：
10.1016/j.yexcr.2015.09.001
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发表时间：
2015-12-10
影响因子：
3.7
通讯作者：
Kim, Song-Ja
中科院分区：
文献类型：
--
作者：
Eo, Seong-Hui;Kim, Dae Won;Kim, Song-Ja
SIRT2是哺乳动物sirtuin蛋白家族的成员，主要存在于细胞质中。它调节许多细胞过程，包括衰老、DNA修复、细胞周期和应激条件下的生存。然而，SIRT2蛋白在正常细胞如原代软骨细胞中的生物学功能和机制还不是很清楚。在这项研究中，我们利用细胞渗透性的PEP-1-SIRT2蛋白检测了SIRT2对兔关节软骨细胞分化和炎症的影响。我们的结果表明，PEP-1-SIRT2以剂量和时间依赖的方式诱导II型胶原丢失和硫酸盐蛋白多糖水平降低，正如Western blotting、Alcian Blue染色和免疫组织化学所检测的那样。此外，PEP-1-SIRT2通过诱导环氧合酶-2(COX-2)和前列腺素E-2(PGE(2))的表达而引起炎症反应。此外，经PEP-1-SIRT2处理后，p38和ERK均被磷酸化。PD98059(PD)抑制ERK可抑制PEP-1-SIRT2诱导的去分化和COX-2的表达。SB203580(SB)抑制p38后，可减轻PEP-1-SIRT2诱导的炎症反应。在连续传代培养过程中，PEP-1-SIRT2诱导的去分化和炎症反应也表现出相同的模式。在扩增至四代的过程中，II型胶原水平下降，而COX-2和SIRT2水平上升并激活ERIC和p38。此外，PEP-1-SIRT2通过ERK途径促进体外培养的兔软骨细胞去分化，并通过ERK和p38途径促进炎症反应。这些发现表明，PEP-1-SIRT2通过ERIC途径诱导兔关节软骨细胞去分化，并通过p38和ERIC途径诱导炎症。(C)2015 Elsevier Inc.保留所有权利。
SIRT2 is a member of the mammalian sirtuin protein family, primarily found in the cytoplasm. It regulates numerous cellular processes including aging, DNA repair, cell cycle, and survival under stress conditions. However, the biological function and mechanism of the SIRT2 protein was not well understood in normal cells such as primary chondrocytes. In this study, we examined the effects of SIRT2 on differentiation and inflammation in rabbit articular chondrocytes by using a cell-permeative PEP-1-SIRT2 protein. Our results indicate that PEP-1-SIRT2-induced a loss of type II collagen and decreased sulfate proteoglycan levels in a dose- and time-dependent manner, as examined by Western blotting, alcian blue staining, and immunohistochemistry. Furthermore, PEP-1-SIRT2 caused an inflammatory response by inducing the expression of cyclooxygenase-2 (COX-2) and prostaglandin E-2 (PGE(2)). In addition, after treatment with PEP-1-SIRT2, phosphorylation of both p38 and ERK was observed. Inhibition of ERK with PD98059 (PD) suppressed PEP-1-SIRT2-induced dedifferentiation and COX-2 expression. Reduction in PEP-1-SIRT2-induced inflammatory response was observed upon inhibition of p38 by SB203580 (SB). The same pattern was demonstrated in PEP-1-SIRT2-induced dedifferentiation and inflammatory response during culture with serial passages. During expansion to four passages, levels of type II collagen decreased, whereas levels of COX-2 and SIRT2 increased and activated ERIC and p38. Furthermore, PEP-1-SIRT2 enhances dedifferentiation through the ERK pathway and inflammatory response through the ERK and p38 pathways in rabbit chondrocytes in vitro. These findings suggest that PEP-1-SIRT2 induces dedifferentiation via the ERIC pathway and inflammation through the p38 and ERIC pathways in rabbit articular chondrocytes. (C) 2015 Elsevier Inc. All rights reserved.