BMP4 Mediates Oxidative Stress-induced Retinal Pigment Epithelial Cell Senescence and Is Overexpressed in Age-related Macular Degeneration

• Published in: The Journal of biological chemistry 2009-04, Vol.284 (14), p.9529-9539
• Main Authors: Zhu, DanHong, Wu, Jian, Spee, Christine, Ryan, Stephen J., Hinton, David R.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Bone Morphogenetic Protein 4 - genetics; Bone Morphogenetic Protein 4 - metabolism; Cell Cycle; Cells, Cultured; Cellular Senescence - physiology; Gene Expression Regulation; Humans; Macular Degeneration - metabolism; Middle Aged; Molecular Basis of Cell and Developmental Biology; Oxidative Stress; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Retinal Pigment Epithelium - metabolism; Smad Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M809393200

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-p21Cip1/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 p21Cip1/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.