Matrix metalloproteinase inhibitors suppress transforming growth factor-β-induced subcapsular cataract formation
Matrix metalloproteinase inhibitors suppress transforming growth factor-β-induced subcapsular cataract formation
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DOI：
10.2353/ajpath.2006.041089
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发表时间：
2006-01-01
影响因子：
6
通讯作者：
West-Mays, JA
中科院分区：
文献类型：
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作者：
Dwivedi, DJ;Pino, G;West-Mays, JA
多效性形态原转化生长因子-β（TGFO）在纤维化病理学（包括前囊下白内障（ASC））的发展中起重要作用。ASC的形成涉及透镜上皮细胞增殖增加，并通过上皮-间充质转化为肌成纤维细胞，从而在透镜囊下形成不透明斑块。在这项研究中，我们使用先前建立的TGF β诱导的大鼠白内障模型来探讨基质金属蛋白酶（MMPs）在ASC形成中的作用。用TGFO处理切除的大鼠晶状体导致MMP-2和MMP-9的分泌增强。重要的是，用两种不同的MMP抑制剂（MMPIs），广谱抑制剂GM 6001和MMP-2/9特异性抑制剂共同治疗，抑制TGF β诱导的ASC变化，包括透镜上皮细胞的上皮-间充质转化。使用抗-E-钙粘蛋白抗体，我们发现，条件培养基与TGF β治疗的晶状体含有72 kd的E-钙粘蛋白片段，指示E-钙粘蛋白脱落。这是伴随着减弱的E-钙粘蛋白mRNA水平。与经TGF β处理的晶状体相比，经TGF β和MMPIs共同处理的晶状体的条件培养基显示出减弱的E-钙粘蛋白片段水平。总之，这些发现表明，TGF β诱导的E-钙粘蛋白脱落在透镜中是由MMP介导的，并且这种现象的抑制可能解释了MMP抑制ASC斑块形成的机制。
The pleotropic morphogen transforming growth factor-beta (TGFO) plays an important role in the development of fibrotic pathologies, including anterior subcapsular cataracts (ASCs). ASC formation involves increased proliferation and transition of lens epithelial cells into myofibroblasts, through epithelial-mesenchymal transformation that results in opaque plaques beneath the lens capsule. in this study, we used a previously established TGF beta-induced rat cataract model to explore the role of matrix metalloproteinases (MMPs) in ASC formation. Treatment of excised rat lenses with TGFO resulted in enhanced secretion of MMP-2 and MMP-9. Importantly, co-treatment with two different MMP inhibitors (MMPIs), the broad spectrum inhibitor GM6001 and an MMP-2/9-specific inhibitor, suppressed TGF beta-induced ASC changes, including the epithelial-mesenchymal transformation of lens epithelial cells. Using an anti-E-cadherin antibody, we revealed that conditioned media from lenses treated with TGF beta contained a 72-kd E-cadherin fragment, indicative of E-cadherin shedding. This was accompanied by attenuated levels of E-cadherin mRNA. Conditioned media from lenses co-treated with TGF beta and MMPIs exhibited attenuated levels of the E-cadherin fragment compared with those from TGF beta-treated lenses. Together, these findings demonstrate that TGF beta-induced E-cadherin shedding in the lens is mediated by MMPs and that suppression of this phenomenon might explain the mechanism by which MMPIs inhibit ASC plaque formation.