The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes.
The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes.
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ERK 和 mTOR 相互抑制参与 PLCγ1 介导的人骨关节炎软骨细胞 MMP-13 表达
DOI：
10.3390/ijms160817857
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发表时间：
2015-08-04
影响因子：
5.6
通讯作者：
Xia C
中科院分区：
文献类型：
--
作者：
Liu Z;Cai H;Zheng X;Zhang B;Xia C
ERK激活是否决定骨关节炎（OA）发病机制中基质合成或降解的问题目前仍存在争议。我们前期研究表明，plc - γ - 1和mTOR参与OA软骨基质代谢。研究plc - γ - 1、mTOR和ERK在OA基质降解中的相互作用将有助于未来在OA预防和治疗中操纵ERK的尝试。在这里，培养的人正常软骨细胞和OA软骨细胞分别用不同的抑制剂处理或用表达载体转染。Western blotting分析ERK、p-ERK、plc - γ1、p- plc - γ1、mTOR、p-mTOR和MMP-13的水平。结果表明，ERK在人OA软骨细胞中的表达水平低于人正常关节软骨细胞，ERK的上调可以促进基质的合成，包括人OA软骨细胞中MMP-13水平的降低和Aggrecan水平的升高。此外，在人OA软骨细胞中观察到plc γ - 1/ERK轴以及mTOR和ERK的相互抑制。有趣的是，活化的ERK对plc - γ -1转化的OA软骨细胞中MMP-13的表达没有抑制作用。结合我们之前的研究，plc - γ1对MMP-13激活ERK无效的部分原因可能是plc - γ1/mTOR轴对plc - γ1/ERK轴的抑制作用。因此，本研究提示，ERK和mTOR的相互抑制参与了plc γ1介导的人OA软骨细胞中MMP-13的表达，对了解OA的发病机制及预防和治疗具有重要意义。
The issue of whether ERK activation determines matrix synthesis or degradation in osteoarthritis (OA) pathogenesis currently remains controversial. Our previous study shows that PLCγ1 and mTOR are involved in the matrix metabolism of OA cartilage. Investigating the interplays of PLCγ1, mTOR and ERK in matrix degradation of OA will facilitate future attempts to manipulate ERK in OA prevention and therapy. Here, cultured human normal chondrocytes and OA chondrocytes were treated with different inhibitors or transfected with expression vectors, respectively. The levels of ERK, p-ERK, PLCγ1, p-PLCγ1, mTOR, p-mTOR and MMP-13 were then evaluated by Western blotting analysis. The results manifested that the expression level of ERK in human OA chondrocytes was lower than that in human normal articular chondrocytes, and the up-regulation of ERK could promote matrix synthesis, including the decrease in MMP-13 level and the increase in Aggrecan level in human OA chondrocytes. Furthermore, the PLCγ1/ERK axis and a mutual inhibition of mTOR and ERK were observed in human OA chondrocytes. Interestingly, activated ERK had no inhibitory effect on MMP-13 expression in PLCγ1-transformed OA chondrocytes. Combined with our previous study, the non-effective state of ERK activation by PLCγ1 on MMP-13 may be partly attributed to the inhibition of the PLCγ1/mTOR axis on the PLCγ1/ERK axis. Therefore, the study indicates that the mutual inhibition of ERK and mTOR is involved in PLCγ1-mediated MMP-13 expression in human OA chondrocytes, with important implication for the understanding of OA pathogenesis as well as for its prevention and therapy.