Periostin in vitreoretinal diseases

Abstract

Proliferative vitreoretinal diseases such as diabetic retinopathy, proliferative vitreoretinopathy (PVR), and age-related macular degeneration are a leading cause of decreased vision and blindness in developed countries. In these diseases, retinal fibro(vascular) membrane (FVM) formation above and beneath the retina plays an important role. Gene expression profiling of human FVMs revealed significant upregulation of periostin. Subsequent analyses demonstrated increased periostin expression in the vitreous of patients with both proliferative diabetic retinopathy and PVR. Immunohistochemical analysis showed co-localization of periostin with α-SMA and M2 macrophage markers in FVMs. In vitro, periostin blockade inhibited migration and adhesion induced by PVR vitreous and transforming growth factor-β2 (TGF-β2). In vivo, a novel single-stranded RNAi agent targeting periostin showed the inhibitory effect on experimental retinal and choroidal FVM formation without affecting the viability of retinal cells. These results indicated that periostin is a pivotal molecule for FVM formation and a promising therapeutic target for these proliferative vitreoretinal diseases.

Keywords: Age-related macular degeneration; Choroid; Epiretinal membranes; Fibrosis; Fibrovascular membranes; Genome-wide gene expression profiling; Mouse model of laser-induced choroidal neovascuarization; Mouse model of oxygen-induced retinal neovascularization; Neovascularization; Proliferative diabetic retinopathy; Proliferative vitreoretinopathy; Retina; Single-stranded RNA interference; Vitreoretinal disease.

Fig. 1

Proliferative vitreoretinal diseases. a Proliferative diabetic retinopathy (PDR). b Proliferative vitreoretinopathy (PVR). c Age-related macular degeneration (AMD). d High myopia

Fig. 2

Presumed mechanism of fibrovascular membrane formation induced by periostin-involving pathologic conditions in eyes with proliferative diabetic retinopathy (PDR). First, retinal ischemia may induce an upregulation in the expression of the CCL2, CCL3, and CCL4 genes which attract monocytes to the diabetic retina. Second, M-CSF released from diabetic retina transforms the recruited monocytes into M2-like macrophages. Third, IL-13 released from the Th2 cells in the retina further polarizes to activated M2 macrophages. Fourth, the polarized M2 macrophages and retinal pericytes produce periostin that promotes retinal neovascularization and fibrosis by Akt phosphorylation via integrin αvβ3. In parallel, the ischemia also stimulates the production of VEGF by retinal glial cells and vascular endothelial cells. These processes are likely to be important in promoting M2 macrophage-involved FVM formation in diabetic retinas

Fig. 3

Presumed mechanism of fibrous membrane formation induced by periostin-involving pathologic conditions in eyes with proliferative vitreoretinopathy (PVR). Ocular injury causes the enhancement of TGFβ2 production and dispersion of RPE cells onto the retina. TGFβ2 induces trans-differentiation of RPE cells into myofibroblasts resulting in periostin production. Periostin acts in an autocrine fashion to stimulate FAK and AKT phosphorylation via the αV integrin, promoting cell proliferation, adhesion and migration, etc., leading to the fibrous membrane formation

Fig. 4

Structure of novel class of single-stranded RNAi agent. Novel class of RNAi agent was prepared as single-stranded RNA oligomers that self-anneal as shown. Nucleotides in red indicate the sense strand of the target (periostin), nucleotides in yellow are the antisense strand, and nucleotides in blue are the scaffold