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What determines the switch between atrophic and neovascular forms of age related macular degeneration? - the role of BMP4 induced senescence.

Zhu D, Deng X, Xu J, Hinton DR - Aging (Albany NY) (2009)

Bottom Line: The genetic and molecular pathways that lead to these diverse phenotypes are currently under investigation.In contrast, in neovascular AMD lesions, BMP4 expression in RPE is low, possibly a result of local expression of pro-inflammatory mediators.Thus, BMP4 may be involved in the molecular switch determining which phenotypic pathway is taken in the progression of AMD.

View Article: PubMed Central - PubMed

Affiliation: Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, CA 90033, USA.

ABSTRACT
Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, targets the retinal pigment epithelium (RPE), a monolayer of cells at the back of the eye. As AMD progresses, it can develop into two distinct forms of late AMD: "dry," atrophic AMD, characterized by RPE senescence and geographic RPE loss, and "wet," neovascular AMD, characterized by RPE activation with abnormal growth of choroidal vessels. The genetic and molecular pathways that lead to these diverse phenotypes are currently under investigation. We have found that bone morphogenetic protein-4 (BMP4) is differentially expressed in atrophic and neovascular AMD. In atrophic AMD, BMP4 is highly expressed in RPE, and mediates oxidative stress induced RPE senescencein vitro via Smad and p38 pathways. In contrast, in neovascular AMD lesions, BMP4 expression in RPE is low, possibly a result of local expression of pro-inflammatory mediators. Thus, BMP4 may be involved in the molecular switch determining which phenotypic pathway is taken in the progression of AMD.

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Related in: MedlinePlus

Diagramillustrating the progression of early age related macular degeneration(AMD) into 2 divergent late stages and the potential role of BMP4 as aswitch between these pathways. Chronic stressors such as oxidative stresscan promote the expression of BMP4 in the retinal pigment epithelium (RPE)and induce RPE senescence as part of the phenotype of early AMD. If BMP4expression is sustained, it could lead to RPE apoptosis and geographicatrophy. In other individuals, activation of the senescence activatedsecretory pathway and expression of pro-inflammatory mediators could resultin increased expression of interleukin (IL)-8, decreased expression of BMP4and increased expression of vascular endothelial growth factor (VEGF)resulting in neovascular AMD with choroidal angiogenesis.
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Figure 1: Diagramillustrating the progression of early age related macular degeneration(AMD) into 2 divergent late stages and the potential role of BMP4 as aswitch between these pathways. Chronic stressors such as oxidative stresscan promote the expression of BMP4 in the retinal pigment epithelium (RPE)and induce RPE senescence as part of the phenotype of early AMD. If BMP4expression is sustained, it could lead to RPE apoptosis and geographicatrophy. In other individuals, activation of the senescence activatedsecretory pathway and expression of pro-inflammatory mediators could resultin increased expression of interleukin (IL)-8, decreased expression of BMP4and increased expression of vascular endothelial growth factor (VEGF)resulting in neovascular AMD with choroidal angiogenesis.

Mentions: Age-related maculardegeneration (AMD) is the leading cause of irreversible blindness in theelderly [1-2]. Considerable evidence supports the opinion that the retinalpigment epithelium (RPE), a monolayer of cells between the light sensitivephotoreceptors and the vascular choroid, is a primary site of pathology in thedisease [1-5]. The RPE provides support for the photoreceptors and plays acritical role in the visual cycle; thus, degeneration and loss of RPE lead tosecondary degeneration of photoreceptor cells [3]. Early AMD is characterizedby the presence of extracellular deposits, or drusen, beneath the RPE.Increasing numbers of large drusen predispose to the development of the late blinding forms of the disease which canmanifest in two disparate ways. In late, "dry" AMD,geographic loss of RPE occurs in the macular region, while in the lateneovascular or "wet" form of the disease, there is abnormal growth of choroidalvessels under the retina which leak fluid and may progress to form a disciformscar (Figure 1) [1-5]. Pathogenic mechanisms for AMD include both genetic andenvironmentalfactors related to primary RPE senescence, alterationsin the complement pathway, increased inflammation, changes in the balance ofgrowth factors, excessive lipofuscinaccumulation, and oxidativestress [5]. Major genetic risk factors for AMD, including Complement Factor Hand HTRA1 variants, appear to predispose to both atrophic and neovascular AMD[6,7]; only recently has a genetic variant been identified that specificallypredisposes to the atrophic form [8]. Consequently, there is considerableinterest in further establishing the factors that mediate the "molecularswitch" that may determine which late form of the disease an individualdevelops.


What determines the switch between atrophic and neovascular forms of age related macular degeneration? - the role of BMP4 induced senescence.

Zhu D, Deng X, Xu J, Hinton DR - Aging (Albany NY) (2009)

Diagramillustrating the progression of early age related macular degeneration(AMD) into 2 divergent late stages and the potential role of BMP4 as aswitch between these pathways. Chronic stressors such as oxidative stresscan promote the expression of BMP4 in the retinal pigment epithelium (RPE)and induce RPE senescence as part of the phenotype of early AMD. If BMP4expression is sustained, it could lead to RPE apoptosis and geographicatrophy. In other individuals, activation of the senescence activatedsecretory pathway and expression of pro-inflammatory mediators could resultin increased expression of interleukin (IL)-8, decreased expression of BMP4and increased expression of vascular endothelial growth factor (VEGF)resulting in neovascular AMD with choroidal angiogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806048&req=5

Figure 1: Diagramillustrating the progression of early age related macular degeneration(AMD) into 2 divergent late stages and the potential role of BMP4 as aswitch between these pathways. Chronic stressors such as oxidative stresscan promote the expression of BMP4 in the retinal pigment epithelium (RPE)and induce RPE senescence as part of the phenotype of early AMD. If BMP4expression is sustained, it could lead to RPE apoptosis and geographicatrophy. In other individuals, activation of the senescence activatedsecretory pathway and expression of pro-inflammatory mediators could resultin increased expression of interleukin (IL)-8, decreased expression of BMP4and increased expression of vascular endothelial growth factor (VEGF)resulting in neovascular AMD with choroidal angiogenesis.
Mentions: Age-related maculardegeneration (AMD) is the leading cause of irreversible blindness in theelderly [1-2]. Considerable evidence supports the opinion that the retinalpigment epithelium (RPE), a monolayer of cells between the light sensitivephotoreceptors and the vascular choroid, is a primary site of pathology in thedisease [1-5]. The RPE provides support for the photoreceptors and plays acritical role in the visual cycle; thus, degeneration and loss of RPE lead tosecondary degeneration of photoreceptor cells [3]. Early AMD is characterizedby the presence of extracellular deposits, or drusen, beneath the RPE.Increasing numbers of large drusen predispose to the development of the late blinding forms of the disease which canmanifest in two disparate ways. In late, "dry" AMD,geographic loss of RPE occurs in the macular region, while in the lateneovascular or "wet" form of the disease, there is abnormal growth of choroidalvessels under the retina which leak fluid and may progress to form a disciformscar (Figure 1) [1-5]. Pathogenic mechanisms for AMD include both genetic andenvironmentalfactors related to primary RPE senescence, alterationsin the complement pathway, increased inflammation, changes in the balance ofgrowth factors, excessive lipofuscinaccumulation, and oxidativestress [5]. Major genetic risk factors for AMD, including Complement Factor Hand HTRA1 variants, appear to predispose to both atrophic and neovascular AMD[6,7]; only recently has a genetic variant been identified that specificallypredisposes to the atrophic form [8]. Consequently, there is considerableinterest in further establishing the factors that mediate the "molecularswitch" that may determine which late form of the disease an individualdevelops.

Bottom Line: The genetic and molecular pathways that lead to these diverse phenotypes are currently under investigation.In contrast, in neovascular AMD lesions, BMP4 expression in RPE is low, possibly a result of local expression of pro-inflammatory mediators.Thus, BMP4 may be involved in the molecular switch determining which phenotypic pathway is taken in the progression of AMD.

View Article: PubMed Central - PubMed

Affiliation: Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, CA 90033, USA.

ABSTRACT
Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, targets the retinal pigment epithelium (RPE), a monolayer of cells at the back of the eye. As AMD progresses, it can develop into two distinct forms of late AMD: "dry," atrophic AMD, characterized by RPE senescence and geographic RPE loss, and "wet," neovascular AMD, characterized by RPE activation with abnormal growth of choroidal vessels. The genetic and molecular pathways that lead to these diverse phenotypes are currently under investigation. We have found that bone morphogenetic protein-4 (BMP4) is differentially expressed in atrophic and neovascular AMD. In atrophic AMD, BMP4 is highly expressed in RPE, and mediates oxidative stress induced RPE senescencein vitro via Smad and p38 pathways. In contrast, in neovascular AMD lesions, BMP4 expression in RPE is low, possibly a result of local expression of pro-inflammatory mediators. Thus, BMP4 may be involved in the molecular switch determining which phenotypic pathway is taken in the progression of AMD.

Show MeSH
Related in: MedlinePlus