Elevated Aqueous Humour Tissue Inhibitor of Matrix Metalloproteinase-1 and Connective Tissue Growth Factor in Pseudoexfoliation Syndrome

Abstract

Abstract: : Purpose: Pseudoexfoliation sydrome (PXF), an age-related systemic disorder of extracellular matrix characterised by progressive accumulation of a fibrillar extracelluar material in many ocular tissues, was recently found to be associated with an increased expression of transforming growth factor-ß₁ (TGFß₁) in the aqueous humour. As concern has been raised regarding anti-TGFß therapy which can potentially disrupt the maintenance of anterior chamber-associated immune deviation (ACAID), we explored the levels of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9) and connective tissue growth factor (CTGF) in aqueous humour as these may represent alternative therapeutic targets. Methods:Aqueous humour samples were collected from patients who underwent routine cataract surgery. All patient were categorised into four main groups namely, pseudoexfoliation syndrome(PXF), primary open angle glaucoma (POAG), uveitis and control. The PXF group was further subcategorised into three grades based on the density of the exfoliative material observed on biomicroscopy, as well as with or without glaucoma. TIMP-1, MMP-9 and CTGF (Fibrogen,Inc.) levels were measured using enzyme immunoassay (ELISA). Results: Eyes with PXF (n=56) had significantly higher aqueous humour TIMP-1 concentration (mean ± SE, 9.76±1.10ng/ml) compared with the controls (n=112, 5.73±0.43ng/ml, P<0.01). Similarly, the CTGF levels in PXF eyes (n=36, 4.38±0.65ng/ml) were higher than the controls (n=29, 2.35± 0.46ng/ml, P<0.05). The MMP-9 levels were low in all samples measured with no statistical difference between groups. The CTGF concentration in PXF glaucoma group is significantly higher compared with PXF eyes without glaucoma (6.03±1.09ng/ml vs 2.73±0.45ng/ml, P<0.01). Conclusions:A raised TIMP-1 level and a low MMP-9 level in aqueous humour of PXF eyes may imply a down-regulation in net proteolytic activity. The increased CTGF concentration supports the proposed fibrotic pathology of PXF. This process could potentially play a role in the pathogenesis of PXF outflow obstruction because of reduced matrix degradation and increased fibrogenic activity in the trabecular meshwork. Regulation of MMP/TIMP expression and anti-CTGF therapy may offer potential therapeutic avenues for controlling PXF-associated ocular morbidity.

Keywords: aqueous • extracellular matrix • growth factors/growth factor receptors