Cause and Effect Relationship between Changes in Scleral Matrix Metallopeptidase-2 Expression and Myopia Development in Mice
Cause and Effect Relationship between Changes in Scleral Matrix Metallopeptidase-2 Expression and Myopia Development in Mice
复制标题
小鼠巩膜基质金属肽酶2表达变化与近视发生的因果关系
DOI：
10.1016/j.ajpath.2018.04.011
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发表时间：
2018-08-01
影响因子：
6
通讯作者：
Zhou, Xiangtian
中科院分区：
文献类型：
--
作者：
Zhao, Fei;Zhou, Qingyi;Zhou, Xiangtian
近视是一种严重损害视力的疾病，其中巩膜生物力学强度的降低与蛋白酶上调相关，导致胶原框架变薄和细胞外基质成分发生变化。基质金属肽酶 (MMP)-2 是介导这些改变的已知蛋白酶之一。为了确定MMP-2上调是否先于近视发展，评估了Mmp2基因功能的获得和丧失对小鼠屈光发展和形觉剥夺性近视的直接影响。注射腺相关病毒血清型8包装的Mmp2过表达载体（AAV8-Mmp2）4周后，巩膜MMP-2上调在正常视觉环境下伴随着明显的近视。相比之下，与注射不相关的乱序序列的眼睛相比，用靶向Mmp2的shRNA包装的AAV8可抑制形式剥夺引起的MMP-2表达上升54%，并减少近视发展23%。由于 MMP-2 蛋白表达水平的相反变化对近视进展具有相应的影响，因此这种蛋白酶的上调有助于诱发这种情况。 MMP-2 上调与近视发展之间存在因果关系的观点得到了证明，与 Cre 阴性同窝小鼠 (Mmp(2fl/fl)) 相比，成纤维细胞特异性 Mmp2 缺失 (S100 α 4(cre)Mmp(2fl/fl)) 小鼠的形状剥夺性近视发展减弱了 27%。因此，MMP-2是抑制近视进展的潜在药物靶点。
Myopia is a serious sight-compromising condition in which decreases in scleral biomechanical strength are associated with protease up-regulation resulting in thinning of its collagenous framework and changes in the extracellular matrix composition. Matrix metallopeptidase (MMP)-2 is one of the known proteases mediating these alterations. To determine whether MMP-2 up-regulation precedes myopia development, the direct effects of gain and loss in Mmp2 gene function were evaluated on refractive development and form deprivation myopia in mice. Four weeks after injecting an adeno-associated virus serotype 8 packaged Mmp2 overexpression vector (AAV8-Mmp2), scleral MMP-2 up-regulation was accompanied by significant myopia in a normal visual environment. In contrast, AAV8 packaging with shRNA targeting Mmp2 inhibited rises in MMP-2 expression induced by form deprivation by 54% and reduced myopia development by 23% compared with eyes injected with an irrelevant scrambled sequence. Because opposing changes in MMP-2 protein expression levels had corresponding effects on myopia progression, up-regulation of this protease contributes to inducing this condition. This notion of a cause-and-effect relationship between MMP-2 up-regulation and myopia development is supported by showing that form-deprived myopia development was attenuated by 27% in fibroblast-specific Mmp2 deletion (S100 alpha 4(cre)Mmp(2fl/fl)) mice relative to Cre-negative littermates (Mmp(2fl/fl)). Therefore, MMP-2 is a potential drug target for inhibiting myopia progression.