Age-related macular degeneration (AMD), the leadingcause of blindness in the elderly, targets the retinal pigment epithelium(RPE), a monolayer of cells at the back of the eye. As AMD progresses, itcan 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 ofchoroidal vessels. The genetic and molecular pathways that lead to thesediverse phenotypes are currently under investigation. We have found thatbone morphogenetic protein-4 (BMP4) is differentially expressed in atrophicand neovascular AMD. In atrophic AMD, BMP4 is highly expressed in RPE, andmediates oxidative stress induced RPE senescencein vitro via Smadand p38 pathways. In contrast, in neovascular AMD lesions, BMP4 expressionin RPE is low, possibly a result of local expression of pro-inflammatorymediators. Thus, BMP4 may be involved in the molecular switch determiningwhich phenotypic pathway is taken in the progression of AMD.