Age-Related Macular Degeneration and the Extracellular Matrix
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《新英格兰医药杂志》
Macular degeneration is a class of blinding disorders characterized by changes in the macula, the central area of the neural retina that is responsible for high-acuity vision (see Figure 1). Such disorders are the leading causes of irreversible visual loss in elderly persons in the Western world. Newly emerging evidence implicates abnormalities in specific components of the extracellular matrix in these eye diseases. For example, in this issue of the Journal, Stone and coworkers (pages 346–353) report missense mutations in a gene encoding an extracellular-matrix protein known as fibulin 5 in patients with the highly prevalent age-related form of macular degeneration.
Figure 1. The Macula of a Patient with Age-Related Macular Degeneration.
The yellow deposits, known as drusen, lie beneath the retinal pigmented epithelium and are the clinical hallmark of this disease.
Other fibulin genes have also been implicated in macular degeneration. In 1999, Stone and colleagues1 discovered that a mutation in the fibulin 3 gene causes a rare, early-onset form of macular degeneration known as malattia leventinese (Doyne's honeycomb retinal dystrophy) that is characterized by a distinctive radial pattern of macular deposits. Others have shown that a single mutation in the fibulin 6 gene is associated with a relatively common phenotype of age-related macular degeneration (AMD) in a single large family.2
The fibulins are a recently identified family of six extracellular-matrix proteins that have roles in the assembly and stabilization of supramolecular extracellular-matrix complexes. Fibulins contain multiple calcium-binding domains that mediate interaction with extracellular-matrix proteins including elastin and laminin. Fibulin 5 is abundantly expressed in tissues and organs that are rich in elastic fibers, including the aorta, the lungs, the uterus, and the skin. It is thought to serve as a link between cell-surface receptors (such as integrins) and extracellular elastic fibers and to regulate their assembly. As a consequence of their involvement in the elaboration and stabilization of the extracellular matrix, the fibulins are thought to be important in the processes of organogenesis, vasculogenesis, fibrogenesis, and tumorigenesis. In humans, some fibulin 5 mutations lead to cutis laxa, a disease that is characterized by loose skin and a reduction in the numbers of elastic fibers. In mice with an inactivated fibulin 5 gene, disorganized elastic-fiber networks develop, resulting in loose skin, aortic abnormalities, and lung defects — but it has not been determined whether elastin-related abnormalities develop in the eyes of such mice.
It is significant that each of the identified fibulin mutations is associated with an ocular disease phenotype that manifests itself at the interface between the retinal pigmented epithelium and Bruch's membrane (see Figure 2). Bruch's membrane is a stratified extracellular-matrix complex composed of a thick elastic layer flanked on either side by a collagenous layer and then a basement membrane. Over the years, numerous histopathological studies have shown that Bruch's membrane undergoes substantial changes in association with aging, and the earliest detectable pathologic changes related to AMD are found at this location. These include the buildup of lipids and cholesterol and the accumulation of abnormal deposits between Bruch's membrane and the retinal pigmented epithelium. The most prominent of these deposits are known as drusen (German for "bumps"). Although a cause-and-effect relationship has not been established, large numbers and extensive areas (to the point of confluence) of drusen, particularly in the macula, have long been recognized as potent risk factors for AMD. On the basis of their composition, drusen are likely to be a manifestation of chronic local inflammatory events.3,4
Figure 2. The Interface between the Retinal Pigmented Epithelium and Bruch's Membrane.
At the core of Bruch's membrane, a stratified complex of the extracellular matrix, is an elastic layer that consists of cross-linked elastin fibers. Bordering the elastic layer are two layers of collagen fibrils known as the inner and outer collagenous layers. Next to the outer collagenous layer is a basal lamina associated with a network of capillaries called the choriocapillaris. A second basal lamina elaborated by the retinal pigmented epithelium is adjacent to the inner collagenous layer. Drusen — extracellular deposits commonly associated with early AMD — form at the interface between the inner collagenous layer and the basal lamina of the retinal pigmented epithelium. Patients with mutations in the fibulin 5 gene have numerous small drusen that are referred to clinically as basal laminar or cuticular drusen.
Collectively, the linkage of fibulin mutations to types of macular degeneration with distinct phenotypes of drusen reinforces the pathologic significance of these deposits and the key role of the interface between the retinal pigmented epithelium and Bruch's membrane in the pathobiology of AMD. How do mutant fibulins contribute to abnormalities in the structure and function of Bruch's membrane, and what is the relationship between mutant fibulin and drusen formation? One possibility is that the mutant protein is misfolded and inefficiently secreted from cells of the retinal pigmented epithelium and thus triggers the degeneration of these cells and the accumulation of inflammatory deposits at the interface between Bruch's membrane and the epithelium. Such a mechanism is postulated for the mutant fibulin 3 that gives rise to malattia leventinese. The mutant fibulin 3 accumulates within retinal pigmented epithelial cells and between this epithelium and Bruch's membrane but not within most drusen.5
Stone and coworkers suggest that reduced levels of mutant fibulin 5, or alterations in its elastin-binding properties, could alter the normal assembly or stability of elastin fibers in Bruch's membrane. They also speculate that fibulin 5 mutations could interfere with the normal adhesion of retinal pigmented epithelial cells to the Bruch's membrane complex, resulting in the detachment of the epithelial monolayer from its substrate — an occurrence that has been observed in patients with fibulin 5 mutations.
Although the percentage of cases of AMD that were associated with fibulin 5 mutations in the study by Stone et al. was small, the data linking abnormalities of the extracellular matrix with AMD and other macular degenerative diseases are mounting. Further investigation should help to clarify the contribution of fibulin mutations, as well as possible mutations in other genes associated with the microfibril–elastic fiber system, to the overall incidence of AMD. Future studies should also help to elucidate the structural and functional roles of the fibulins and their binding partners in relation to the adhesion of retinal pigmented epithelial cells and the function of Bruch's membrane. As they have already begun to do, such studies should eventually lead to the genetic dissection of AMD into multiple related disorders and to the characterization of the molecular abnormalities that are responsible for specific disease phenotypes.
Source Information
From the Center for the Study of Macular Degeneration, Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara.
References
Stone EM, Lotery AJ, Munier FL, et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet 1999;22:199-202.
Schultz DW, Klein ML, Humpert AJ, et al. Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. Hum Mol Genet 2003;12:3315-3323.
Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705-732.
Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134:411-431.
Marmorstein LY, Munier FL, Arsenijevic Y, et al. Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc Natl Acad Sci U S A 2002;99:13067-13072.(Lincoln V. Johnson, Ph.D.)
Figure 1. The Macula of a Patient with Age-Related Macular Degeneration.
The yellow deposits, known as drusen, lie beneath the retinal pigmented epithelium and are the clinical hallmark of this disease.
Other fibulin genes have also been implicated in macular degeneration. In 1999, Stone and colleagues1 discovered that a mutation in the fibulin 3 gene causes a rare, early-onset form of macular degeneration known as malattia leventinese (Doyne's honeycomb retinal dystrophy) that is characterized by a distinctive radial pattern of macular deposits. Others have shown that a single mutation in the fibulin 6 gene is associated with a relatively common phenotype of age-related macular degeneration (AMD) in a single large family.2
The fibulins are a recently identified family of six extracellular-matrix proteins that have roles in the assembly and stabilization of supramolecular extracellular-matrix complexes. Fibulins contain multiple calcium-binding domains that mediate interaction with extracellular-matrix proteins including elastin and laminin. Fibulin 5 is abundantly expressed in tissues and organs that are rich in elastic fibers, including the aorta, the lungs, the uterus, and the skin. It is thought to serve as a link between cell-surface receptors (such as integrins) and extracellular elastic fibers and to regulate their assembly. As a consequence of their involvement in the elaboration and stabilization of the extracellular matrix, the fibulins are thought to be important in the processes of organogenesis, vasculogenesis, fibrogenesis, and tumorigenesis. In humans, some fibulin 5 mutations lead to cutis laxa, a disease that is characterized by loose skin and a reduction in the numbers of elastic fibers. In mice with an inactivated fibulin 5 gene, disorganized elastic-fiber networks develop, resulting in loose skin, aortic abnormalities, and lung defects — but it has not been determined whether elastin-related abnormalities develop in the eyes of such mice.
It is significant that each of the identified fibulin mutations is associated with an ocular disease phenotype that manifests itself at the interface between the retinal pigmented epithelium and Bruch's membrane (see Figure 2). Bruch's membrane is a stratified extracellular-matrix complex composed of a thick elastic layer flanked on either side by a collagenous layer and then a basement membrane. Over the years, numerous histopathological studies have shown that Bruch's membrane undergoes substantial changes in association with aging, and the earliest detectable pathologic changes related to AMD are found at this location. These include the buildup of lipids and cholesterol and the accumulation of abnormal deposits between Bruch's membrane and the retinal pigmented epithelium. The most prominent of these deposits are known as drusen (German for "bumps"). Although a cause-and-effect relationship has not been established, large numbers and extensive areas (to the point of confluence) of drusen, particularly in the macula, have long been recognized as potent risk factors for AMD. On the basis of their composition, drusen are likely to be a manifestation of chronic local inflammatory events.3,4
Figure 2. The Interface between the Retinal Pigmented Epithelium and Bruch's Membrane.
At the core of Bruch's membrane, a stratified complex of the extracellular matrix, is an elastic layer that consists of cross-linked elastin fibers. Bordering the elastic layer are two layers of collagen fibrils known as the inner and outer collagenous layers. Next to the outer collagenous layer is a basal lamina associated with a network of capillaries called the choriocapillaris. A second basal lamina elaborated by the retinal pigmented epithelium is adjacent to the inner collagenous layer. Drusen — extracellular deposits commonly associated with early AMD — form at the interface between the inner collagenous layer and the basal lamina of the retinal pigmented epithelium. Patients with mutations in the fibulin 5 gene have numerous small drusen that are referred to clinically as basal laminar or cuticular drusen.
Collectively, the linkage of fibulin mutations to types of macular degeneration with distinct phenotypes of drusen reinforces the pathologic significance of these deposits and the key role of the interface between the retinal pigmented epithelium and Bruch's membrane in the pathobiology of AMD. How do mutant fibulins contribute to abnormalities in the structure and function of Bruch's membrane, and what is the relationship between mutant fibulin and drusen formation? One possibility is that the mutant protein is misfolded and inefficiently secreted from cells of the retinal pigmented epithelium and thus triggers the degeneration of these cells and the accumulation of inflammatory deposits at the interface between Bruch's membrane and the epithelium. Such a mechanism is postulated for the mutant fibulin 3 that gives rise to malattia leventinese. The mutant fibulin 3 accumulates within retinal pigmented epithelial cells and between this epithelium and Bruch's membrane but not within most drusen.5
Stone and coworkers suggest that reduced levels of mutant fibulin 5, or alterations in its elastin-binding properties, could alter the normal assembly or stability of elastin fibers in Bruch's membrane. They also speculate that fibulin 5 mutations could interfere with the normal adhesion of retinal pigmented epithelial cells to the Bruch's membrane complex, resulting in the detachment of the epithelial monolayer from its substrate — an occurrence that has been observed in patients with fibulin 5 mutations.
Although the percentage of cases of AMD that were associated with fibulin 5 mutations in the study by Stone et al. was small, the data linking abnormalities of the extracellular matrix with AMD and other macular degenerative diseases are mounting. Further investigation should help to clarify the contribution of fibulin mutations, as well as possible mutations in other genes associated with the microfibril–elastic fiber system, to the overall incidence of AMD. Future studies should also help to elucidate the structural and functional roles of the fibulins and their binding partners in relation to the adhesion of retinal pigmented epithelial cells and the function of Bruch's membrane. As they have already begun to do, such studies should eventually lead to the genetic dissection of AMD into multiple related disorders and to the characterization of the molecular abnormalities that are responsible for specific disease phenotypes.
Source Information
From the Center for the Study of Macular Degeneration, Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara.
References
Stone EM, Lotery AJ, Munier FL, et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet 1999;22:199-202.
Schultz DW, Klein ML, Humpert AJ, et al. Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. Hum Mol Genet 2003;12:3315-3323.
Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705-732.
Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134:411-431.
Marmorstein LY, Munier FL, Arsenijevic Y, et al. Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc Natl Acad Sci U S A 2002;99:13067-13072.(Lincoln V. Johnson, Ph.D.)