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Anuja Siwakoti, Jennifer Robertson, Judith West-Mays; Altered expression of TGFβ1 and MMP-9 results in elevated intraocular pressure in mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5632. doi: https://doi.org/.
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Extracellular matrix (ECM) remodeling is thought to have profound effects on tissue architecture and associated function. It is important to study the contributions of TGFβ1 and MMP-9, two genes that are known to regulate the dynamics of the ECM and suspected to control aqueous outflow. Our lab has previously shown that overexpression of TGFβ, which stimulates matrix accumulation, results in altered morphology, cataracts and ocular hypertension in rodents. We have also demonstrated that TGFβ-induced cataracts can be mitigated through inhibition of the matrix metalloproteinases (MMP): MMP-2 and MMP-9. In the current study, we investigated how the loss of MMP-9 expression affects the TGFβ-induced changes in intraocular pressure (IOP).
The expression of a TGFβ1 transgene, under control of the αA-crystalin promoter, was used to target TGFβ expression to the anterior chamber of the mouse eye (J. Clin. Invest.,101,625-634,1998). The TGFβ1 transgenic mice were then bred onto a MMP-9 knockout (KO) background. Transgenic, KO and wild type littermates aged 1 month to 4 months were used. IOP was measured using the Tonolab rebound tonometer. The animals were sacrificed and eyes were enucleated. The eyes were processed and paraffin sectioned for histological and immunofluorescence studies. Immunoflourescence was performed to detect αSMA, collagen IV and N-cadherin molecules.
Our results demonstrate that lens-specific expression of TGFβ1 in mice results in significant increase in IOP accompanied by altered morphology of the anterior segment. TGFβ1 transgenic mice bred onto the MMP-9 KO background exhibited a further increase in IOP. Interestingly, MMP-9 KO animals (without the TGFβ1 transgene), which exhibited normal angle morphology, had increased IOP levels compared to their wild-type littermates.
These results indicate that alterations in expression levels of the extracellular matrix remodelling molecules, TGFβ1and MMP-9, can impact the regulation of IOP. In particular, the loss of MMP-9 expression resulted in increased IOP levels, in the absence of any overt morphological changes. Further investigation into the mechanisms of MMP-9 activity in the anterior angle may give clues to how extracellular matrix remodeling participates in ocular hypertension and glaucoma.
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