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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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IL-8 protein concentration in culture medium measured by ELISA. ARPE-19cells were treated with 150 uM H2O2 in culture mediumwith 10% fetal bovine serum for 2 hours and allowed to recover in stressor-freeARPE medium for 22 hours. The procedure was repeated to generate the nexttreatment cycle. Thetwice treated cells were allowed to stay in 1% serum ARPE medium for 72hours after stress before proceeding to further analytic assays.The culture media from control and senescent RPE cells were collected andused directly for ELISA measurement. IL-8 secretion level was measured in pg/ml usinghuman IL-8 ELISA Kit (BioLegend, Inc., San Diego, CA) according tomanufacturer's instructions. The level of IL-8 secretion shown here wasaveraged from a triplicate of each sample and from 3 independent repeats ofH2O2 treatments. Student's t test was used forstatistical analysis (**; p < 0.0005).
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Figure 3: IL-8 protein concentration in culture medium measured by ELISA. ARPE-19cells were treated with 150 uM H2O2 in culture mediumwith 10% fetal bovine serum for 2 hours and allowed to recover in stressor-freeARPE medium for 22 hours. The procedure was repeated to generate the nexttreatment cycle. Thetwice treated cells were allowed to stay in 1% serum ARPE medium for 72hours after stress before proceeding to further analytic assays.The culture media from control and senescent RPE cells were collected andused directly for ELISA measurement. IL-8 secretion level was measured in pg/ml usinghuman IL-8 ELISA Kit (BioLegend, Inc., San Diego, CA) according tomanufacturer's instructions. The level of IL-8 secretion shown here wasaveraged from a triplicate of each sample and from 3 independent repeats ofH2O2 treatments. Student's t test was used forstatistical analysis (**; p < 0.0005).

Mentions: It remainsunanswered why some patients develop atrophic AMD while others develop theneovascular form of the disease. The switch between dry and wet AMD may berelated to differences in the microenvironment created by senescent RPE cells,which secrete a number of cytokines and growth factors [25]. The definedcomponents of this "senescence associated secretory phenotype" (SASP) includeelements associated with inflammation, and angiogenesis, such as interleukin(IL)-6 and IL-8 [26-28]. We have found that RPE cells induced into senescenceby chronic oxidative stress secrete 4 times higher IL-8 than non-senescent RPEcells (Figure 3). IL-8 promotes angiogenesis by increasing the proliferation, survival andmigration of endothelial cells and promotes inflammation by increasingneutrophil chemotaxis and degranulation [29-31]. Together these findingssuggest that chronic oxidative stress increases the premature senescence ofRPE. If RPE do not go down the cell deathpathway to atrophic AMD, the senescent RPE may secrete high levels of IL-8,which in turn stimulate inflammation and angiogenesis. But what about thefinding that neovascular AMD lesions show minimal levels of BMP4? In other celltypes, pro-inflammatory mediators such as tumor necrosis factor (TNF)-alphahave been shown to downregulate BMP4 expression [32]. In the absence of BMP4,neovascular endothelial cells, stimulated by increased expression of vascularendothelial growth factor, and without the growth inhibitory senescence andcell death effects mediated by BMP4, would be in a permissive environ-ment forangiogenesis [5]. This idea is further supported by the finding that whenneovascular AMD lesions undergo subsequent scar formation, with degenerationand loss of neovascular endothelial cells, there is a concomitant increase inBMP4 expression (Figure 2).


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)

IL-8 protein concentration in culture medium measured by ELISA. ARPE-19cells were treated with 150 uM H2O2 in culture mediumwith 10% fetal bovine serum for 2 hours and allowed to recover in stressor-freeARPE medium for 22 hours. The procedure was repeated to generate the nexttreatment cycle. Thetwice treated cells were allowed to stay in 1% serum ARPE medium for 72hours after stress before proceeding to further analytic assays.The culture media from control and senescent RPE cells were collected andused directly for ELISA measurement. IL-8 secretion level was measured in pg/ml usinghuman IL-8 ELISA Kit (BioLegend, Inc., San Diego, CA) according tomanufacturer's instructions. The level of IL-8 secretion shown here wasaveraged from a triplicate of each sample and from 3 independent repeats ofH2O2 treatments. Student's t test was used forstatistical analysis (**; p < 0.0005).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: IL-8 protein concentration in culture medium measured by ELISA. ARPE-19cells were treated with 150 uM H2O2 in culture mediumwith 10% fetal bovine serum for 2 hours and allowed to recover in stressor-freeARPE medium for 22 hours. The procedure was repeated to generate the nexttreatment cycle. Thetwice treated cells were allowed to stay in 1% serum ARPE medium for 72hours after stress before proceeding to further analytic assays.The culture media from control and senescent RPE cells were collected andused directly for ELISA measurement. IL-8 secretion level was measured in pg/ml usinghuman IL-8 ELISA Kit (BioLegend, Inc., San Diego, CA) according tomanufacturer's instructions. The level of IL-8 secretion shown here wasaveraged from a triplicate of each sample and from 3 independent repeats ofH2O2 treatments. Student's t test was used forstatistical analysis (**; p < 0.0005).
Mentions: It remainsunanswered why some patients develop atrophic AMD while others develop theneovascular form of the disease. The switch between dry and wet AMD may berelated to differences in the microenvironment created by senescent RPE cells,which secrete a number of cytokines and growth factors [25]. The definedcomponents of this "senescence associated secretory phenotype" (SASP) includeelements associated with inflammation, and angiogenesis, such as interleukin(IL)-6 and IL-8 [26-28]. We have found that RPE cells induced into senescenceby chronic oxidative stress secrete 4 times higher IL-8 than non-senescent RPEcells (Figure 3). IL-8 promotes angiogenesis by increasing the proliferation, survival andmigration of endothelial cells and promotes inflammation by increasingneutrophil chemotaxis and degranulation [29-31]. Together these findingssuggest that chronic oxidative stress increases the premature senescence ofRPE. If RPE do not go down the cell deathpathway to atrophic AMD, the senescent RPE may secrete high levels of IL-8,which in turn stimulate inflammation and angiogenesis. But what about thefinding that neovascular AMD lesions show minimal levels of BMP4? In other celltypes, pro-inflammatory mediators such as tumor necrosis factor (TNF)-alphahave been shown to downregulate BMP4 expression [32]. In the absence of BMP4,neovascular endothelial cells, stimulated by increased expression of vascularendothelial growth factor, and without the growth inhibitory senescence andcell death effects mediated by BMP4, would be in a permissive environ-ment forangiogenesis [5]. This idea is further supported by the finding that whenneovascular AMD lesions undergo subsequent scar formation, with degenerationand loss of neovascular endothelial cells, there is a concomitant increase inBMP4 expression (Figure 2).

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