Insulin Rescues the Oncostatin M-induced, but not the BMP7-induced Retinal Degeneration in Transgenic Mice

Abstract

Abstract: : Purpose: To test whether expression of human insulin in the lens can rescue the OSM- and BMP7-induced retinal apoptosis in transgenic mice. Methods: We generated transgenic mice that ectopically express BMP7 or the C-terminal truncated version (206 aa) of OSM under the control of the αA crystallin promoter. These mice were mated to mice that express human insulin under the same promoter. Phenotypic analyses included histology, immunohistochemistry and in situ hybridization using standard protocols. Results: Expression of OSM resulted abnormal ocular development characterized by posterior migration of lens epithelial cells, persistence and hyperproliferation of the hyaloid vasculature, vitreal and sub-retinal hemorrage, and rapid retinal degeneration associated with decreased proliferation of retinal progenitors, premature expression of retinal cell markers and up-regulation of p21 expression. TUNEL assays and Caspase 3 activation indicated postnatal massive apoptosis in transgenic mice retinas, compared with non-transgenic controls. Concomitant transgenic expression of human insulin in the lens completely rescued the OSM-induced phenotype. However, insulin did not rescue the retinal degeneration phenotype observed in mice expressing Bmp7 in the lens. Conclusions: These results indicate that OSM and Bmp7 induce apoptosis in the retina by two different mechanisms and suggest that the OSM-induced apoptosis is mediated my activation of caspase 9 and that the Bmp7-induced apoptosis is mediated by activation of caspase 8. Ongoing experiments are designed to characterize these pathways.

Keywords: apoptosis/cell death • retinal degenerations: cell biology • cytokines/chemokines