Induction of tissue inhibitor of matrix metalloproteinase-2 by cholesterol depletion leads to the conversion of proMMP-2 into active MMP-2 in human dermal fibroblasts
Induction of tissue inhibitor of matrix metalloproteinase-2 by cholesterol depletion leads to the conversion of proMMP-2 into active MMP-2 in human dermal fibroblasts
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DOI：
10.3858/emm.2010.42.1.004
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发表时间：
2010-01-31
影响因子：
12.8
通讯作者：
Chung, Jin Ho
中科院分区：
文献类型：
--
作者：
Kim, Sangmin;Oh, Jang-Hee;Chung, Jin Ho
胆固醇是细胞膜的主要成分之一，在囊泡运输和细胞信号传导中发挥作用。我们研究了胆固醇对人真皮成纤维细胞基质金属蛋白酶 2 (MMP-2) 激活的影响。我们发现，胆固醇消耗剂甲基-β-环糊精 (MPCD) 可以剂量依赖性地增加基质金属蛋白酶组织抑制剂 2 (TIMP-2) 的表达和活性形式 MMP-2 (64 kD)。相反，胆固醇消耗诱导的 TIMP-2 表达和 MMP-2 激活受到胆固醇补充的抑制。然后我们研究了胆固醇消耗对TIMP-2表达的调节机制。我们发现 JNK 和 ERK 的磷酸化因胆固醇消耗而显着增加。此外，MEK 抑制剂 U0126 和 JNK 抑制剂 SP600125 分别显着降低胆固醇消耗诱导的 TIMP-2 表达和 MMP-2 激活。低剂量的重组 TIMP-2 (100 ng/ml) 增加了活性 MMP-2 (64 kD) 的水平，而高剂量的 TIMP-2 (>= 200 ng/ml) 降低了活性 MMP-2 (64 kD) 的水平。综上所述，我们认为胆固醇消耗诱导 TIMP-2 导致人真皮成纤维细胞中 proMMP-2 (72 kD) 转化为活性 MMP-2 (64 kD)。
Cholesterol is one of major components of cell membrane and plays a role in vesicular trafficking and cellular signaling. We investigated the effects of cholesterol on matrix metalloproteinase-2 (MMP-2) activation in human dermal fibroblasts. We found that tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) expression and active form MMP-2 (64 kD) were dose-dependently increased by methyl-beta-cyclodextrin (MPCD), a cholesterol depletion agent. In contrast, cholesterol depletion-induced TIMP-2 expression and MMP-2 activation were suppressed by cholesterol repletion. Then we investigated the regulatory mechanism of TIMP-2 expression by cholesterol depletion. We found that the phosphorylation of JNK as well as ERK was significantly increased by cholesterol depletion. Moreover, cholesterol depletion-induced TIMP-2 expression and MMP-2 activation was significantly decreased by MEK inhibitor U0126, and JNK inhibitor SP600125, respectively. While a low dose of recombinant TIMP-2 (100 ng/ml) increased the level of active MMP-2 (64 kD), the high dose of TIMP-2 (>= 200 ng/ml) decreased the level of active MMP-2 (64 kD). Taken together, we suggest that the induction of TIMP-2 by cholesterol depletion leads to the conversion of proMMP-2 (72 kD) into active MMP-2 (64 kD) in human dermal fibroblasts.