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      Matrix Metalloproteinases in Age-Related Macular Degeneration (AMD)

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          Abstract

          Age-related macular degeneration (AMD) is a complex, multifactorial and progressive retinal disease affecting millions of people worldwide. In developed countries, it is the leading cause of vision loss and legal blindness among the elderly. Although the pathogenesis of AMD is still barely understood, recent studies have reported that disorders in the regulation of the extracellular matrix (ECM) play an important role in its etiopathogenesis. The dynamic metabolism of the ECM is closely regulated by matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). The present review focuses on the crucial processes that occur at the level of the Bruch’s membrane, with special emphasis on MMPs, TIMPs, and the polymorphisms associated with increased susceptibility to AMD development. A systematic literature search was performed, covering the years 1990–2020, using the following keywords: AMD, extracellular matrix, Bruch’s membrane, MMPs, TIMPs, and MMPs polymorphisms in AMD. In both early and advanced AMD, the pathological dynamic changes of ECM structural components are caused by the dysfunction of specific regulators and by the influence of other regulatory systems connected with both genetic and environmental factors. Better insight into the pathological role of MMP/TIMP complexes may lead to the development of new strategies for AMD treatment and prevention.

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          Drusen proteome analysis: an approach to the etiology of age-related macular degeneration.

          Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch's membrane and are risk factors for developing age-related macular degeneration (AMD). The progression of AMD might be slowed or halted if the formation of drusen could be modulated. To work toward a molecular understanding of drusen formation, we have developed a method for isolating microgram quantities of drusen and Bruch's membrane for proteome analysis. Liquid chromatography tandem MS analyses of drusen preparations from 18 normal donors and five AMD donors identified 129 proteins. Immunocytochemical studies have thus far localized approximately 16% of these proteins in drusen. Tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin were the most common proteins observed in normal donor drusen whereas crystallin was detected more frequently in AMD donor drusen. Up to 65% of the proteins identified were found in drusen from both AMD and normal donors. However, oxidative protein modifications were also observed, including apparent crosslinked species of tissue metalloproteinase inhibitor 3 and vitronectin, and carboxyethyl pyrrole protein adducts. Carboxyethyl pyrrole adducts are uniquely generated from the oxidation of docosahexaenoate-containing lipids. By Western analysis they were found to be more abundant in AMD than in normal Bruch's membrane and were found associated with drusen proteins. Carboxymethyl lysine, another oxidative modification, was also detected in drusen. These data strongly support the hypothesis that oxidative injury contributes to the pathogenesis of AMD and suggest that oxidative protein modifications may have a critical role in drusen formation.
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            Is there new hope for therapeutic matrix metalloproteinase inhibition?

            Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that form a family of 24 members in mammals. Evidence of the pathological roles of MMPs in various diseases, combined with their druggability, has made them attractive therapeutic targets. Initial drug discovery efforts focused on the roles of MMPs in cancer progression, and more than 50 MMP inhibitors have been investigated in clinical trials in various cancers. However, all of these trials failed. Reasons for failure include the lack of inhibitor specificity and insufficient knowledge about the complexity of the disease biology. MMPs are also known to be involved in several inflammatory processes, and there are new therapeutic opportunities for MMP inhibitors to treat such diseases. In this Review, we discuss the recent advances made in understanding the role of MMPs in inflammatory diseases and the therapeutic potential of MMP inhibition in those conditions.
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              Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease.

              Age-related macular degeneration (AMD), a blinding disorder that compromises central vision, is characterized by the accumulation of extracellular deposits, termed drusen, between the retinal pigmented epithelium and the choroid. Recent studies in this laboratory revealed that vitronectin is a major component of drusen. Because vitronectin is also a constituent of abnormal deposits associated with a variety of diseases, drusen from human donor eyes were examined for compositional similarities with other extracellular disease deposits. Thirty-four antibodies to 29 different proteins or protein complexes were tested for immunoreactivity with hard and soft drusen phenotypes. These analyses provide a partial profile of the molecular composition of drusen. Serum amyloid P component, apolipoprotein E, immunoglobulin light chains, Factor X, and complement proteins (C5 and C5b-9 complex) were identified in all drusen phenotypes. Transcripts encoding some of these molecules were also found to be synthesized by the retina, retinal pigmented epithelium, and/or choroid. The compositional similarity between drusen and other disease deposits may be significant in view of the recently established correlation between AMD and atherosclerosis. This study suggests that similar pathways may be involved in the etiologies of AMD and other age-related diseases.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                18 August 2020
                August 2020
                : 21
                : 16
                : 5934
                Affiliations
                [1 ]Clinical University Hospital of Valladolid, Av. Ramón y Cajal, 3, 47003 Valladolid, Spain; luisonrubia91@ 123456gmail.com (L.G.-O.); franciscojavier.valentin@ 123456gmail.com (F.J.V.-B.); pastor@ 123456ioba.med.uva.es (J.C.P.)
                [2 ]Institute of Applied Ophthalmobiology (IOBA), University of Valladolid, 47011 Valladolid, Spain; rosa@ 123456ioba.med.uva.es
                [3 ]Cooperative Health Network for Research in Ophthalmology (Oftared), National Institute of Health Carlos III, ISCIII, 28040 Madrid, Spain
                [4 ]Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; gonzalez@ 123456usal.es
                [5 ]Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca—CSIC, 37007 Salamanca, Spain
                Author notes
                Author information
                https://orcid.org/0000-0003-3563-2369
                https://orcid.org/0000-0002-2062-3243
                https://orcid.org/0000-0002-1811-1417
                https://orcid.org/0000-0002-2726-6795
                https://orcid.org/0000-0001-5934-7306
                https://orcid.org/0000-0001-7699-4388
                https://orcid.org/0000-0002-6463-4227
                Article
                ijms-21-05934
                10.3390/ijms21165934
                7460693
                32824762
                71ee7ec7-cf56-47e4-b840-62d4102935ef
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 July 2020
                : 12 August 2020
                Categories
                Review

                Molecular biology
                age-related macular degeneration,extracellular matrix,bruch’s membrane,matrix metalloproteinases,tissue inhibitors of metalloproteinases,mmps polymorphisms

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