Abstract
The retinal pigment epithelium is a primary site of pathology in age-related macular degeneration. Oxidative stress and senescence are both thought to be important mediators of macular degeneration pathogenesis. We demonstrate here that bone morphogenetic protein-4 is highly expressed in the retinal pigment epithelium and adjacent extracellular matrix of patients with dry age-related macular degeneration. In vitro studies revealed that sublethal oxidative stress increased bone morphogenetic protein-4 expression in retinal pigment epithelial cells, and both bone morphogenetic protein-4 and persistent mild oxidative stress can induce retinal pigment epithelial cell senescence through p53-p21(Cip1/WAF1)-Rb pathway. We further demonstrate that bone morphogenetic protein-4 acts as a mediator in oxidative stress-induced senescence and that this mediator function is via Smad and the p38 signaling pathway to increase and activate p53 and p21(Cip1/WAF1) and decrease phospho-Rb. Oxidative stress-induced senescence can be blocked by Chordin-like, an antagonist of bone morphogenetic protein-4, or SB203580, a phospho-p38 inhibitor. Our results suggest that oxidative stress and bone morphogenetic protein-4 may interact to promote retinal pigment epithelial cell senescence and that bone morphogenetic protein-4 may represent a novel therapeutic target to inhibit the progressive effects of oxidative stress and senescence in dry age-related macular degeneration.
Highlights
Age-related macular degeneration (AMD)2 is the leading cause of irreversible blindness in the developed world
First identified as a state of irreversible growth arrest after serial cultivation of cells in vitro, premature senescence has been implicated as a potentially important pathophysiologic mediator of retinal pigment epithelium (RPE) atrophy and loss in Geographic atrophy (GA) [4]. Markers of senescence, such as telomere shortening and altered gene expression have been identified in RPE cells exposed to advanced glycation end products (AGE), which are found in association with Bruch membrane in AMD [19]
We evaluated the expression of BMP4 in early and late dry AMD and investigated the interplay between BMP4 signaling, oxidative stress, and the induction of RPE senescence
Summary
Age-related macular degeneration (AMD)2 is the leading cause of irreversible blindness in the developed world. We evaluated the expression of BMP4 in early and late dry AMD and investigated the interplay between BMP4 signaling, oxidative stress, and the induction of RPE senescence.
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