Extracellular Matrix (ECM) Aging in the Retina: The Role of Matrix Metalloproteinases (MMPs) in Bruch's Membrane Pathology and Age-Related Macular Degeneration (AMD)

Abstract

The extracellular matrix (ECM) is a collagen-based scaffold that provides structural support and regulates nutrient transport and cell signaling. ECM homeostasis depends on a dynamic balance between synthesis and degradation, the latter being primarily mediated by matrix metalloproteinases (MMPs). These enzymes are secreted as pro-forms and require activation to degrade ECM components. Their activity is modulated by tissue inhibitors of metalloproteinases (TIMPs). Aging disrupts this balance, leading to the accumulation of oxidized, cross-linked, and denatured matrix proteins, thereby impairing ECM function. Bruch's membrane, a penta-laminated ECM structure in the eye, plays a critical role in supporting photoreceptor and retinal pigment epithelium (RPE) health. Its age-related thickening and decreased permeability are associated with impaired nutrient delivery and waste removal, contributing to the pathogenesis of age-related macular degeneration (AMD). In AMD, MMP dysfunction is characterized by the reduced activation and sequestration of MMPs, which further limits matrix turnover. This narrative review explores the structural and functional changes in Bruch's membrane with aging, the role of MMPs in ECM degradation, and the relevance of these processes to AMD pathophysiology, highlighting emerging regulatory mechanisms and potential therapeutic targets.

Keywords: Bruch’s membrane; age-related macular degeneration (AMD); aging; extracellular matrix (ECM); matrix metalloproteinases (MMPs).

Figure 1

The visual unit of the human eye. (a) Situated between the RPE and the choroidal blood supply, Bruch’s membrane serves as a crucial transport interface, mediating the passage of both free and carrier-bound nutrients, antioxidants, and trace metals to the photoreceptor–RPE complex. It also functions as the final barrier for the efflux of fluids, metabolic waste, and membranous debris. The integrity of these transport routes is vital for maintaining photoreceptor and RPE cell survival. (b) Electron microscopy image of Bruch’s membrane from human tissue, revealing its distinct penta-laminar organization [17,18]. BM, Bruch’s membrane; RPE, retinal pigment epithelium; A, basement membrane of the RPE; B, inner collagenous layer; C, elastin layer; D, outer collagenous layer; E, basement membrane of the choriocapillaris. Bar marker, 0.5 µm.

Figure 2

Schematic to show the age-related changes in the structure and function of Bruch’s membrane highlighting the risk of transition to pathology in the elderly. AMD, age-related macular degeneration; RPE, retinal pigment epithelium.

Figure 3

Oxidative stress-induced structural and functional alterations in aging Bruch’s membrane. Photoreceptors generate toxic byproducts including bis-retinoids [33,34,35,36], lipid–protein aggregates [37,38,39,40], and reactive carbonyl compounds [37,38,41,42] through rhodopsin activation, photooxidation of PUFAs [43], and lipid peroxidation [37,38,40,44]. These metabolites undergo limited degradation in the RPE and accumulate as lipofuscin [45,46,47,48] or are deposited onto Bruch’s membrane [11,40,44,49,50,51,52]. Over time, this leads to ECM disruption, impaired transport, and structural degeneration of Bruch’s membrane [10,12,53,54,55,56], contributing to age-related pathology. A2E, N-retinylidene-N-retinylethanolamine; AGEs, advanced glycation end products; AT-RL, all-trans retinal; CEP, carboxyethylpyrrole; ECM, extracellular matrix; PUFAs, polyunsaturated fatty acids; RPE, retinal pigment epithelium.

Figure 4

Fluid transport across aging human Bruch’s membrane. Hydraulic conductivity of Bruch’s membrane declines exponentially with age, as shown in 56 donors aged 9 to 91. Older individuals, including some healthy controls, approach the failure threshold, increasing the risk of fluid buildup and RPE detachment. AMD donors show even lower conductivity, suggesting accelerated membrane dysfunction (modified from Refs. [71,73,74]).

Figure 5

Albumin diffusion across aging human Bruch’s membrane. Diffusion decreases exponentially with age, reaching a functional threshold in the elderly (modified from Ref. [76]).

Figure 6

Zymogram to show the various MMP species present in intact human Bruch’s membrane. Zymogram showing pro-MMP2, pro-MMP9, and HMWs in human Bruch’s membrane (adapted from Refs. [97,101,118,119,120,121,122,123]). HMWs, high molecular weight gelatinase species.

Figure 7

The MMP pathway of aging and rejuvenation of Bruch’s membrane. LMMC, large macromolecular weight MMP complex; HMWs, high molecular weight gelatinase species.

Figure 8

Activation of pro-MMP2. Pro-MMP2 is activated on the RPE basolateral surface through a complex with MMP14 and TIMP2 (adapted from Refs. [138,139,140]).

Figure 9

Competing reactions reducing the level of free pro-MMP2 for activation in Bruch’s membrane. Free pro-MMP2 is reduced by matrix binding, covalent complex formation with pro-MMP9 (HMW2), and incorporation into LMMC particles. In AMD, elevated pro-MMP9 accelerates these reactions, limiting pro-MMP2 activation (adapted from Refs. [123,141]).

Figure 10

Effect of oral saponin or placebo supplementation on rod S2 gradients over two to four months in AMD patients and controls. (A) After two months, placebo-treated subjects (three AMD patients and two controls, open circles) showed little or no change in S2 gradients. In contrast, all AMD patients who received saponins (filled circles) showed improvement (p < 0.005). (B) At four months, S2 gradients in the placebo group remained unchanged. Four AMD patients who continued saponin treatment showed further improvement compared to their two-month values (p < 0.01) (adapted from Ref. [156]). AMD, age-related macular degeneration.

Figure 11

Effect of RPE proliferation on the fluid transporting characteristics of underlying Bruch’s membrane. RPE proliferation enhances the hydraulic conductivity of aged human Bruch’s membrane, likely via MMP activation. In vitro, ARPE-19 cells seeded onto donor membranes improved transport properties after reaching confluence (adapted from Ref. [91]).