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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

Expression of BMP4 in late stages of age related macular degeneration(AMD). Immunohistochemical stains for BMP4 (red chromogen) in retinalpigment epithelium (RPE)/choroid tissue sections from donor eyes withhematoxylin counterstain. In (A) a control individual without AMDshows no apparent BMP4 staining in RPE or choroid. In (B) anindividual with late dry AMD, away from a region of geographic atrophyshows prominent BMP4 immunoreactivity in RPE and in the accumulated drusenmaterial between the RPE and the choroid. In (C) an individual withneovascular form of late AMD shows no apparent BMP4 staining in the RPE orthe neovascular lesion between the RPE and retina. In (D) anindividual with neovascular form of late AMD that further progressed toscar with loss of neovascular channels shows re-expression of BMP4 stainingin cells within and adjacent to the lesion. Note loss of most cells in RPElayer. The institutional review board (IRB) ofthe University of Southern California approved our use of human donor eyes.All procedures conformed to the Declaration of Helsinki forresearchinvolving human subjects.
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Figure 2: Expression of BMP4 in late stages of age related macular degeneration(AMD). Immunohistochemical stains for BMP4 (red chromogen) in retinalpigment epithelium (RPE)/choroid tissue sections from donor eyes withhematoxylin counterstain. In (A) a control individual without AMDshows no apparent BMP4 staining in RPE or choroid. In (B) anindividual with late dry AMD, away from a region of geographic atrophyshows prominent BMP4 immunoreactivity in RPE and in the accumulated drusenmaterial between the RPE and the choroid. In (C) an individual withneovascular form of late AMD shows no apparent BMP4 staining in the RPE orthe neovascular lesion between the RPE and retina. In (D) anindividual with neovascular form of late AMD that further progressed toscar with loss of neovascular channels shows re-expression of BMP4 stainingin cells within and adjacent to the lesion. Note loss of most cells in RPElayer. The institutional review board (IRB) ofthe University of Southern California approved our use of human donor eyes.All procedures conformed to the Declaration of Helsinki forresearchinvolving human subjects.

Mentions: Recently, we reported that bonemorphogenetic protein (BMP)4 is prominently expressed in the RPE and adjacentextracellular matrix of patients with the dry or atrophic form of AMD whencompared to controls (Figure 2A, B). Here, we show that in the wet orneovascular form of the disease (5 patients with surgical excision of choroidalneovascular membranes due to neovascular AMD) there is almost no expression ofBMP4 in the RPE and adjacent neovascular tissues (Figure 2C). Interestingly, incases (3 patients) in which the neovascular lesion had progressed to a fibrousscar, the level of BMP4 expression increased in the RPE and adjacent tissues(Figure 2D). This has led us to the hypothesis that BMP4 may be a molecularswitch participating in the pathway decision thatdetermines which form of late AMD develops.


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)

Expression of BMP4 in late stages of age related macular degeneration(AMD). Immunohistochemical stains for BMP4 (red chromogen) in retinalpigment epithelium (RPE)/choroid tissue sections from donor eyes withhematoxylin counterstain. In (A) a control individual without AMDshows no apparent BMP4 staining in RPE or choroid. In (B) anindividual with late dry AMD, away from a region of geographic atrophyshows prominent BMP4 immunoreactivity in RPE and in the accumulated drusenmaterial between the RPE and the choroid. In (C) an individual withneovascular form of late AMD shows no apparent BMP4 staining in the RPE orthe neovascular lesion between the RPE and retina. In (D) anindividual with neovascular form of late AMD that further progressed toscar with loss of neovascular channels shows re-expression of BMP4 stainingin cells within and adjacent to the lesion. Note loss of most cells in RPElayer. The institutional review board (IRB) ofthe University of Southern California approved our use of human donor eyes.All procedures conformed to the Declaration of Helsinki forresearchinvolving human subjects.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Expression of BMP4 in late stages of age related macular degeneration(AMD). Immunohistochemical stains for BMP4 (red chromogen) in retinalpigment epithelium (RPE)/choroid tissue sections from donor eyes withhematoxylin counterstain. In (A) a control individual without AMDshows no apparent BMP4 staining in RPE or choroid. In (B) anindividual with late dry AMD, away from a region of geographic atrophyshows prominent BMP4 immunoreactivity in RPE and in the accumulated drusenmaterial between the RPE and the choroid. In (C) an individual withneovascular form of late AMD shows no apparent BMP4 staining in the RPE orthe neovascular lesion between the RPE and retina. In (D) anindividual with neovascular form of late AMD that further progressed toscar with loss of neovascular channels shows re-expression of BMP4 stainingin cells within and adjacent to the lesion. Note loss of most cells in RPElayer. The institutional review board (IRB) ofthe University of Southern California approved our use of human donor eyes.All procedures conformed to the Declaration of Helsinki forresearchinvolving human subjects.
Mentions: Recently, we reported that bonemorphogenetic protein (BMP)4 is prominently expressed in the RPE and adjacentextracellular matrix of patients with the dry or atrophic form of AMD whencompared to controls (Figure 2A, B). Here, we show that in the wet orneovascular form of the disease (5 patients with surgical excision of choroidalneovascular membranes due to neovascular AMD) there is almost no expression ofBMP4 in the RPE and adjacent neovascular tissues (Figure 2C). Interestingly, incases (3 patients) in which the neovascular lesion had progressed to a fibrousscar, the level of BMP4 expression increased in the RPE and adjacent tissues(Figure 2D). This has led us to the hypothesis that BMP4 may be a molecularswitch participating in the pathway decision thatdetermines which form of late AMD develops.

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