Matrix Metalloproteinases in Age-Related Macular Degeneration (AMD)

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.

Keywords: Bruch’s membrane; MMPs polymorphisms; age-related macular degeneration; extracellular matrix; matrix metalloproteinases; tissue inhibitors of metalloproteinases.

Figure 1

Age-related macular degeneration (AMD) is an eye disease affecting the macula, a central region in the retina. Individuals affected by AMD in its advanced stage may experience a profound loss of central vision. (A,B) Color pictures of retina with changes typical for early stages of AMD, typified by the presence of numerous large drusen, more or less confluent, and associated (or not) with retinal pigment epithelium (RPE) abnormalities (arrow). (C,D) Color and autofluorescence (AF) pictures of fundus for retina with changes typical for dry AMD. (C) The advanced form of dry AMD is typified by the presence of central geographic atrophy (GA) showing a sharply demarcated atrophic lesion of the outer retina, resulting from the loss of photoreceptors, RPE, and choriocapillaris (asterisk). (D) GA areas typically appear as dark patches in fundus AF images, and can be clearly delineated (asterisk).

Figure 2

(A–F) Color, optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) and AF pictures of fundus for retina with changes typical for wet AMD. (A) Wet AMD is characterized by abnormal angiogenesis (choroidal neovascularization (CNV)), causing recurrent retinal exudation, subretinal hemorrhage, retinal or pigment detachment and, in the final stages of the disease, subretinal fibrosis (disciform scar). (B) AF showing confluent atrophic patches (asterisk) with a banded pattern of increased AF in the junction. The CNV can be seen in the OCT-angiography (black star); (C) the structural OCT enables the identification of the abnormal vascular tree (white star) and the presence of subretinal fluid (arrows) (D). By doing an FFA, we can also confirm the presence of the CNV: (E) Early phase: stippled hyperfluorescence with adjacent masking areas by blood or subretinal fibrosis; (F) Late phase: The hyperfluorescence increases irregularly due to the presence of progressive leakage (black arrow-head).

Figure 3

Mechanisms for Pro Matrix Metalloproteinase Activation. ProMMP-2 is the only MMP activated on the cell surface by MT-1MMP (MMP-14); this activation requires the trimolecular complex MT1-MMP/TIMP-2/proMMP-2 and the dimerization of the MT1-MMP. Extracellular activation is applicable to many secreted MMPs, such as proMMP-1,3,7,8,9,10,12, and 13, which are activated by a wide type of proteinases. Furin-activated, secreted proMMPs, such as proMMP-11, 14, 23, and 28 are activated intracellularly due to the removal of propeptides by the action of proprotein convertases such as furin. MMP: matrix metalloproteinases; TIMP: tissue metalloproteinase inhibitor; Cl: C-terminal domain of TIMP-2; F: furin recognition site; Zn: zinc of the active site.