Raloxifene Upregulated Mesangial Cell MMP-2 Activity via ER-β Through Transcriptional Regulation
Raloxifene Upregulated Mesangial Cell MMP-2 Activity via ER-β Through Transcriptional Regulation
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DOI：
10.1007/s12013-013-9548-1
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发表时间：
2013-11-01
影响因子：
2.6
通讯作者：
Huang, Wenlong
中科院分区：
文献类型：
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作者：
Fang, Ming;Wu, Xin-Chi;Huang, Wenlong
雷洛昔芬是第二代选择性雌激素受体调节剂，在特定组织中发挥雌激素样作用。在本研究中，我们检测了雷洛昔芬对链脲佐菌素诱导的糖尿病小鼠系膜细胞基质金属蛋白酶-2 （MMP-2）活性的影响。雷洛昔芬以剂量依赖性和受体介导的方式增加MMP-2水平。一种针对雌激素受体β (er - β)的抗体阻断了雷洛昔芬对MMP-2表达的影响，表明雷洛昔芬对MMP-2活性的影响是由er - β介导的。此外，在雷洛昔芬模拟下，在MMP-2基因转录中起重要作用的转录因子AP-2过表达。MMP-2的作用被细胞外信号调节激酶/丝裂原活化蛋白激酶（ERK/MAPK）途径的选择性抑制剂PD98059阻断。我们的研究结果表明，雷洛昔芬诱导的MMP-2活性通过ERK/MAPK信号传导AP-2增加功能。此外，我们还发现雷洛昔芬对MMP-2表达的影响是通过其与er - β的结合介导的。然而，在我们研究的这个阶段，(i)我们只能证明与er - β的结合和ERK/MAPK途径的激活都会影响MMP-2的表达，（ii）我们无法建立er - β结合和ERK/MAPK途径激活之间的关系。
Raloxifene, a second-generation selective estrogen receptor modulator, exerts estrogen-like effects in specific tissues. In this present study, we examined the effect of raloxifene on mesangial cell matrix metalloproteinase-2 (MMP-2) activity in streptozotocin-induced diabetic mice. Raloxifene increased the MMP-2 level in a dose-dependent and receptor-mediated manner. An antibody against estrogen receptor-beta (ER-beta) blocked the effect of raloxifene on MMP-2 expression, suggesting that the effect of raloxifene on MMP-2 activity was mediated by ER-beta. In addition, the transcription factor AP-2, that plays an important role in MMP-2 gene transcription, was overexpressed under raloxifene simulation. The effect of MMP-2 was blocked by a selective inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway, PD98059. Our results suggested that raloxifene-induced MMP-2 activity increases function through ERK/MAPK signaling via AP-2. In addition, we also found that the effect of raloxifene on MMP-2 expression was mediated via its binding to ER-beta. However, at this stage of our investigation, (i) we could only show that both the binding to ER-beta and the activation of the ERK/MAPK pathway impacted MMP-2 expression and (ii) we were unable to establish a relationship between ER-beta binding and ERK/MAPK pathway activation.