The dynamic nature of Bruch's membrane

Abstract

Bruch's membrane (BM) is a unique pentalaminar structure, which is strategically located between the retinal pigment epithelium (RPE) and the fenestrated choroidal capillaries of the eye. BM is an elastin- and collagen-rich extracellular matrix that acts as a molecular sieve. BM partly regulates the reciprocal exchange of biomolecules, nutrients, oxygen, fluids and metabolic waste products between the retina and the general circulation. Accumulating evidence suggests that the molecular, structural and functional properties of BM are dependent on age, genetic constitution, environmental factors, retinal location and disease state. As a result, part of the properties of BM are unique to each human individual at a given age, and therefore uniquely affect the development of normal vision and ocular disease.

The changes occurring in BM with age include increased calcification of elastic fibres, increased cross-linkage of collagen fibres and increased turnover of glycosaminoglycans. In addition, advanced glycation end products (AGEs) and fat accumulate in BM.

These age-related changes may not only influence the normal age-related health of photoreceptor cells, but also the onset and progression of diseases like retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Undoubtedly, BM is the site of drusen development. Confluent drusen and uncontrolled activation of the complement cascade are most likely the first signs of AMD. Furthermore, the nature of adhesive interactions between the RPE and BM are instrumental in the development of retinal detachments and proliferative retinal disease. Finally, BM is passively or actively involved in a range of other retinal disorders such as Pseudoxanthoma elasticum (PXE), Sorsby's Fundus Dystrophy and Malattia Leventinese.

Here, we review the dynamic nature of Bruch's membrane, from molecule to man, during development, aging and disease. We propose a simple and straightforward nomenclature for BM deposits. Finally, we attempt to correlate recently published mRNA expression profiles of the RPE and choroid with molecular, structural and functional properties of BM. Our review may shed light on the complex involvement of BM in retinal pathology, notably age-related macular degeneration.

Introduction

In the past, many investigators considered Bruch's membrane (BM) a relatively boring and simple sheet of extracellular matrix, merely occupying space between the retinal pigment epithelium (RPE) and the choroid. Recently, however, interest in BM has increased exponentially; and understandably so, given its strategic location between the retina and the general circulation, and its crucial role in retinal function, aging and ocular disease. The pentalaminar BM structure forms a single functional unit with the RPE and choriocapillaris. It is involved in the essential exchange of numerous biomolecules, oxygen, nutrients and waste products in between these tissues. Given its unique location and structure, BM plays a crucial role in cell–cell communication, cellular differentiation, proliferation or migration, tissue remodelling and in shaping pathologic processes (Takei and Ozanics, 1975, Olson, 1979, Campochiaro et al., 1986, Guymer et al., 1999). The nature of BM is highly dynamic, and depends on genetic factors, environmental burden, the topographic position in the retina, age and disease (Hogan and Alvarado, 1967, Crabb et al., 2002, Klein et al., 2004, Curcio et al., 2005, van Soest et al., 2007, Bhutto et al., 2008, Booij et al., 2009). It has also become clear that BM is the focal point of local and systemic risk factors for initial stages of the most frequent untreatable blinding disorder known to man: age-related macular degeneration (AMD). In addition, BM is primarily or secondarily involved in a number of additional genetically determined ophthalmic disorders such proliferative vitreoretinopathy (PVR) (Stone et al., 1992, Pastor et al., 2002), pseudoxanthoma elasticum (PXE) (Aessopos et al., 1989, van Soest et al., 1997), Marfan syndrome (McKusick et al., 1972, Appel et al., 1979, Beighton et al., 1988), Sorsby's fundus dystrophy (Sorsby and Mason, 1949, Capon et al., 1989, Ayyagari et al., 2000) and others.

Here, we review the existing knowledge on BM, with a focus on its normal structure and function (Section 2) and the role of BM in normal aging and early AMD pathology (Section 3). Finally, we provide an outlook on possible AMD disease prevention or treatment (Section 4).