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      Higher TGF-β1, TGF-β2, MMP-2, and TIMP-1 Levels in the Aqueous Humor of Patients with Acute Primary Angle Closure

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          Abstract

          Purpose: To assess the quantitative differences in the levels of members of the transforming growth factor (TGF-β), matrix metalloproteinase (MMP), and tissue inhibitor of MMP (TIMP) families in the aqueous humor (AH) between patients with acute primary angle closure (APAC) and those with cataract only. Methods: AH samples were collected from 26 patients with APAC and cataract as well as 26 patients with age-related cataract only. Multiplex assays were used to measure the concentrations of TGF-β1, TGF-β2, and TGF-β3; MMP-1, MMP-2, MMP-7, MMP-9, and MMP-10; and TIMP-1 and TIMP-2. Results: The concentrations of TGF-β1, TGF-β2, MMP-2, ( p < 0.001), and TIMP-1 were significantly higher (all p < 0.001) in AH samples from patients with APAC versus cataract only. Conversely, the AH concentrations of MMP-7 ( p = 0.524), MMP-9 ( p = 0.103), MMP-10 ( p = 0.111), and TIMP-2 ( p = 0.059) did not significantly differ between the groups. The concentrations of TGF-β3 and MMP-1 were below the respective detection limits in most AH samples. Conclusion: The AH levels of TGF-β1, TGF-β2, MMP-2, and TIMP-1 were elevated in APAC eyes. Such altered protein levels could induce abnormal deposition of extracellular matrix in the trabecular meshwork, resulting in an increase in aqueous outflow resistance and, thereby, providing a possible explanation of the mechanism of residual glaucoma after cataract surgery.

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          Most cited references 28

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          Matrix metalloproteinases and their inhibitors in connective tissue remodeling.

           J. Woessner (1991)
          Matrix metalloproteinases are an important group of zinc enzymes responsible for degradation of the extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and remodeling and in many disease processes such as arthritis, cancer, periodontitis, and osteoporosis. A matrixin family is defined, comprising at least seven members that range in size from Mr 28,000 to 92,000 and are related in gene sequence to collagenase. All family members are secreted as zymogens that lose peptides of about 10,000 daltons upon activation. Latency is due to a conserved cysteine that binds to zinc at the active center. Latency is overcome by physical (chaotropic agents), chemical (HOCl, mercurials), and enzymatic (trypsin, plasmin) treatments that separate the cysteine residue from the zinc. Expression of the metalloproteinases is switched on by a variety of agents acting through regulatory elements of the gene, particularly the AP-1 binding site. A family of protein inhibitors of Mr 28,500 or less binds strongly and stoichiometrically in noncovalent fashion to inhibit members of the family. The serum protein alpha 2-macroglobulin and relatives are also strongly inhibitory.
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            Proteolytic remodeling of extracellular matrix.

             P. H. Hansen (1995)
            Matrix metalloproteinases and their natural inhibitors are ingredients of a fundamental cellular toolbox for effecting environmental change. These enzymes enable cells to alter their relationship to the environment by directly cleaving structural macromolecules of the extracellular matrix. In addition, evidence is emerging that they also play an important regulatory role in matrix remodeling by catalyzing the processing of inactive matrix metalloproteinase and cytokine precursors.
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              TGFbeta2-induced changes in human trabecular meshwork: implications for intraocular pressure.

              Transforming growth factor (TGF)-beta2 levels are elevated in glaucomatous human aqueous humor. TGFbeta is a cytokine that alters extracellular matrix (ECM) metabolism, and excess ECM has been proposed to increase aqueous outflow resistance in the trabecular meshwork (TM) of glaucomatous eyes. This study was undertaken to investigate effects of TGFbeta2 on secretion of fibronectin and the protease inhibitor plasminogen activator inhibitor (PAI)-1 from human TM cell cultures and perfused human ocular anterior segments. Total RNA was isolated from pooled human TM cell monolayers and used for a gene microarray expression analysis. Supernatants from treated human TM cells were analyzed by ELISA for fibronectin or PAI-1 content. TGFbeta2 effects on intraocular pressure (IOP) were evaluated in a perfused organ culture model using human anterior segments, and eluates were analyzed for fibronectin and PAI-1 content. Overnight treatment of TM cells with TGFbeta2 upregulated multiple ECM-related genes, such as PAI-1. TGFbeta2 also increased secretion of both fibronectin and PAI-1 from TM cells. TGFbeta2 effects on TM cells were blocked by inhibitors of the TGFbeta type I receptor. In perfused human anterior segments, TGFbeta2 treatment elevated IOP and increased eluate fibronectin and PAI-1 content. TGFbeta2 effects on IOP may be transduced by TGFbeta type-I receptor-mediated changes in TM secretion of ECM-related factors such as fibronectin and PAI-1. Modulation of TGFbeta2-induced changes in the ECM may provide a novel and viable approach to the management of glaucoma.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2021
                February 2021
                08 April 2020
                : 64
                : 1
                : 62-67
                Affiliations
                aDepartment of Ophthalmology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
                bXi’an Fourth Hospital, Shaanxi Eye Hospital, Affiliated Xi’an Fourth Hospital, Northwestern Polytechnical University, Xi’an, China
                Author notes
                *Hong Yan, Xi’an Fourth Hospital, Shaanxi Eye Hospital, Affiliated Xi’an Fourth Hospital, Northwestern Polytechnical University, Xi’an, Shaanxi 710004 (China), yhongb@fmmu.edu.cn
                Article
                507762 Ophthalmic Res 2021;64:62–67
                10.1159/000507762
                32259818
                © 2020 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 4, Pages: 6
                Categories
                Research Article

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