Bone Morphogenetic Protein 2: a Potential New Player in the Pathogenesis of Diabetic Retinopathy.

Abstract

Purpose: Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus. Vision loss in DR principally occurs due to breakdown of the blood-retinal barrier (BRB), leading to macular edema, retinal detachment and inner retinal and vitreous hemorrhage. Several growth factors have been shown to play crucial role in the development of these vascular changes; however, the cellular and molecular mechanisms of DR are not yet fully revealed. In the current study we investigated the role of bone morphogenetic protein-2 (BMP2) in DR.

Methods: Using ELISA, Western blotting and immunohistochemistry we examined the changes in the protein levels of BMP2 in diabetic human vitreous and retina in addition to the retinas of streptozotocin-induced diabetic mice. The impact of BMP2 (10 and 50 ng/ml) on barrier function of cultured human retinal endothelial cells (hRECs) was evaluated using the FITC-Dextran flux permeability assay and by measuring the changes in trans-endothelial cell electrical resistance (TER) using the Electric Cell-Substrate Impedance Sensing (ECIS). Furthermore, we tested the pro-inflammatory effects of BMP2 by examining its effect on leukocyte adhesion to hRECs, levels of adhesion molecules and cytokines production. Finally, the effect of BMP2 on the levels of VEGF in cultured rat Muller cells (rMC1) (generous gift form Dr.Vijay Sarthy, (Northwestern University)) was evaluated by ELISA.

Results: Our results show, for the first time, the up-regulation of BMP2 in diabetic human and mouse retinas in addition to its detection in vitreous of patients with proliferative DR (72±7 pg/ml). Furthermore, BMP2 induced VEGF secretion by Muller cells in-vitro; and induced a similar effect to VEGF on hRECs barrier function as seen by the increased permeability to FITC-Dextran and decreased TER measured by ECIS. Meanwhile, BMP2 pro-inflammatory effects were recognized by its ability to induce leukocyte adhesion to the hRECs, intercellular adhesion molecule-1 (ICAM1) and upregulation of interleukin-6 and 8 (IL-6 and IL-8).

Conclusions: Our results showed that BMP2 could be a contributing factor to the microvascular dysfunction during DR via enhancing both pro-angiogenic and inflammatory pathways. Therefore, BMP2 signaling system is a potential therapeutic target to treat DR.

Keywords: 499 diabetic retinopathy • 557 inflammation • 543 growth factors/growth factor receptors