Elevated aqueous humour tissue inhibitor of matrix metalloproteinase-1 and connective tissue growth factor in pseudoexfoliation syndrome

Abstract

Background/aims: Pseudoexfoliation syndrome (PXF) was recently found to be associated with increased expression of transforming growth factor b 1 (TGFb 1 ) in the aqueous humour. As concern has been raised regarding anti-TGFb therapy, which can potentially disrupt the maintenance of anterior chamber associated immune deviation, the authors 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 to determine if these may represent alternative therapeutic targets. Methods: Aqueous humour samples were collected from patients who underwent routine cataract surgery. All patients were categorised into three main groups-PXF, 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 the presence or absence of glaucoma. TIMP-1, MMP-9, and CTGF levels were measured using specific enzyme immunoassays (ELISA). Results: Eyes with PXF had significantly higher aqueous humour TIMP-1 concentration (n = 56, mean (SE), 9.76 (1.10) ng/ml) compared with controls (n = 112, 5.73 (0.43) ng/ml, p,0.01). Similarly, the CTGF level in PXF eyes (n = 36, 4.38 (0.65) ng/ml) was higher than controls (n = 29, 2.35 (0.46) ng/ml, p,0.05). Further, the CTGF concentration in the PXF glaucoma group is significantly higher compared with PXF eyes without glaucoma (6.03 (1.09) ng/ml v 2.73 (0.45) ng/ml, p,0.01). The MMP-9 levels were low and below detection limit in all PXF and control samples with no statistical difference between groups. Conclusion: A raised TIMP-1 level and a low MMP-9 level in aqueous humour of PXF eyes may imply a downregulation in proteolytic activity. The increased CTGF concentration supports the proposed fibrotic pathology of PXF. Regulation of MMP/TIMP expression and anti-CTGF therapy may offer potential therapeutic avenues for controlling PXF associated ocular morbidity.

Individual molecular response to elevated intraocular pressure in perfused postmortem human eyes

“…Other regulated genes with calcification implications, such as CTGF, CALB2, STATH, OGN, and SPARC were also found and could be relevant for the trabecular meshwork. CTGF, which was generally altered by the elevated pressure, is elevated in the aqueous humor of patients with pseudoexfoliation glaucoma (32). Also regulated in most individuals were CALB2, a vitamin D-dependent calcium-binding protein involved in calcium homeostasis and mineralization (25,38), and SPARC, a calcium and collagen binding protein recently proposed to be a collagen chaperone (44).…”

Anti-Connective Tissue Growth Factor Antibody Treatment Reduces Extracellular Matrix Production in Trabecular Meshwork and Lamina Cribrosa Cells

“…We have previously shown that the CTGF levels in AqH of patients with PXFG were significantly higher than in POAG and normal control subjects. 37,38 Therefore, we examined the fibrotic potential of AqH samples from PXFG and POAG patients using nonglaucomatous cataract samples as controls. Exposure of TM and LC cells to AqH from both PXFG and POAG patients significantly increased expression of profibrotic genes.…”

“…37 Pseudoexfoliation and primary open angle glaucoma patients were defined as previously described. 37 Sixteen cataract patients (73.8 6 9.7 years), 14 POAG patients (72.3 6 7.4 years), and 17 PXFG (80.7 6 7.2 years) were recruited and all were age-and sex-matched (P ‡ 0.05). Two to three AqH samples were pooled per experiment, depending on the original sample volume (50-100 lL per patient).…”

“…36 We have previously shown that the CTGF level in the AqH of patients with PXFG was significantly higher than in both POAG and normal control subjects. 37,38 It appears that coordinate expression of TGFb and CTGF is a normal feature of wound healing. However, pathological fibrosis is often attributed to uncontrolled matrix deposition, perhaps mediated by a CTGFenriched microenvironment.…”

Matricellular Proteins in the Trabecular Meshwork: Review and Update

“…104 Given its profibrotic tendencies, it became a protein of interest in surgical models, demonstrating increased expression following glaucoma filtration surgery in rabbits and being associated with an elevated risk of bleb failure. 105,106 The putative role of CTGF in human glaucoma pathophysiology was first identified in pseudoexfoliation syndrome, 107,108 and attention soon focused on how CTGF regulates TM matrix deposition, 109,110 cellular tone, 111 and aqueous outflow facility. 112,113 In one promising recent study, the prostaglandin analog fluprostenol was found to mitigate CTGF-induced fibrogenesis in cultured human TM cells.…”