BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration.
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.
Zhu
Danhong
D
Arnold and Mabel Beckman Macular Research Center, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
Wu
Jian
J
Spee
Christine
C
Ryan
Stephen J
SJ
Hinton
David R
DR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008268:Macular Degeneration / Q000378:metabolism*; D008875:Middle Aged; D018384:Oxidative Stress; D010766:Phosphorylation; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D055415:Bone Morphogenetic Protein 4; D051785:Smad Proteins; D048051:p38 Mitogen-Activated Protein Kinases