Cause and Effect Relationship between Changes in Scleral Matrix Metallopeptidase-2 Expression and Myopia Development in Mice

Abstract

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 (S100a4Mmp2) mice relative to Cre-negative littermates (Mmp2). Therefore, MMP-2 is a potential drug target for inhibiting myopia progression.

The Dynamic Scleral Extracellular Matrix Alterations in Chronic Ocular Hypertension Model of Rats

“…The upregulation of MMP2 in the sclera during the myopia process contributed to the degradation of the collagen and elongation of the eye length ( Rada and Brenza, 1995 ; Rada et al, 1999 ). Reducing scleral MMP2 could alleviate the reduction of COL1 accumulation and retard myopia progression in mice ( Zhao et al, 2018 ). Elastin is usually resistant to proteolysis.…”

“…Concordantly, biomechanical tests of the myopic models showed an increased creep rate and elasticity of the sclera (Phillips et al, 2000;McBrien et al, 2009). Interfering with the expression of MMP2 could slow down myopia development in animal models (Liu et al, 2017;Zhao et al, 2018).…”

“…MMP2 is one of the most important MMPs during the myopia process. The production of MMP2 was demonstrated to increase in animal models of myopia, enhancing the degradation of the scleral ECM components such as COL1 ( Liu et al, 2017 ; Zhao et al, 2018 ). Concordantly, biomechanical tests of the myopic models showed an increased creep rate and elasticity of the sclera ( Phillips et al, 2000 ; McBrien et al, 2009 ).…”

Differential expression of connective tissue growth factor and hepatocyte growth factor in the vitreous of patients with high myopia versus vitreomacular interface disease

“…Alterations in TGF-β2 expression is associated with scleral remodeling in myopia development [14]. MMP-2 upregulation was shown to precede myopia development [15], whereas reduced expression of the tissue inhibitor of metalloproteinase was associated with myopia development [16]. But, the associations of CTGF and HGF with myopia are still unclear.…”

A new angle on myopia therapeutics: Not just a fishing expedition

“…The zebrafish zlum-silencing model focuses attention on myopia mechanisms and therapeutic targets in the sclera [9], where lumican is an important component of the scleral extracellular matrix. Whether lumican is expressed in the retina or choroid À through which visual control of scleral expansion is exercised À is unknown, but unlikely.…”