title: Bone morphogenetic protein 2: a potential new player in the pathogenesis of diabetic retinopathy.
abstract: 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. We examined the changes in the protein levels of BMP2 in human vitreous and retina in addition to the mouse retina of streptozotocin-induced diabetes. To detect the source of BMP2 during diabetes, human retinal endothelial cells (hRECs) were subjected to high glucose (HG) for 5 days and levels of BMP2 protein were analyzed in conditioned media of these cells relative to control. We also evaluated the effect of BMP2 on the levels of VEGF in cultured rat Müller cells (rMC1). In addition, we tested the pro-inflammatory effects of BMP2 by examining its effect on leukocyte adhesion to cultured hRECs, and levels of adhesion molecules and cytokines production. Finally, the effect of different concentrations of BMP2 on permeability of confluent monolayer of hRECs was evaluated using FITC-Dextran flux permeability assay and by measuring Transcellular Electrical Resistance (TER) using Electric Cell-substrate Impedance Sensing (ECIS). 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). In vitro, hRECs showed upregulation of BMP2 in HG conditions suggesting that these cells are a potential source of BMP2 in diabetic conditions. Furthermore, BMP2 induced VEGF secretion by Müller cells in-vitro; and showed a dose response in increasing permeability of cultured hRECs. Meanwhile, BMP2 pro-inflammatory effects were recognized by its ability to induce leukocyte adhesion to the hRECs, intercellular adhesion molecule-1 (ICAM-1) and upregulation of interleukin-6 and 8 (IL-6 and IL-8). These results show that BMP2 could be a contributing growth factor to the development of microvascular dysfunction during DR via enhancing both pro-angiogenic and inflammatory pathways. Our findings suggest BMP2 as a potential therapeutic target to prevent/treat DR.
authors.affiliation: Department of Oral Biology/Anatomy College of Dental Medicine, Georgia Reagents University (Augusta) (GRU(A)), USA; Vision Discovery Institute, Medical College of Georgia, GRU(A), USA; Oral and Dental Research Division, Department of Surgery and Medicine, National Research Center, Egypt.
authors.forename: Khaled A
authors.initials: KA
authors.lastname: Hussein
authors.affiliation: Department of Oral Biology/Anatomy College of Dental Medicine, Georgia Reagents University (Augusta) (GRU(A)), USA; Vision Discovery Institute, Medical College of Georgia, GRU(A), USA.
authors.forename: Karishma
authors.initials: K
authors.lastname: Choksi
authors.affiliation: Department of Oral Biology/Anatomy College of Dental Medicine, Georgia Reagents University (Augusta) (GRU(A)), USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Akeel
authors.affiliation: Vision Discovery Institute, Medical College of Georgia, GRU(A), USA; Department of Biological Sciences, Rabigh College of Science and Arts, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Saif
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Department of Oral Biology/Anatomy College of Dental Medicine, Georgia Reagents University (Augusta) (GRU(A)), USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Megyerdi
authors.affiliation: Department of Oral Biology/Anatomy College of Dental Medicine, Georgia Reagents University (Augusta) (GRU(A)), USA; Vision Discovery Institute, Medical College of Georgia, GRU(A), USA; Department of Anatomy, Mansoura Faculty of Medicine, Mansoura, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Sherbiny
authors.affiliation: Department of Ophthalmology, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Nawaz
authors.affiliation: Department of Ophthalmology, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abu El-Asrar
authors.affiliation: Department of Oral Biology/Anatomy College of Dental Medicine, Georgia Reagents University (Augusta) (GRU(A)), USA; Vision Discovery Institute, Medical College of Georgia, GRU(A), USA; Department of Anatomy, Mansoura Faculty of Medicine, Mansoura, Egypt; Department of Ophthalmology, Medical College of Georgia, GRU(A), USA; Department of Cellular Biology and Anatomy, GRU(A), USA. Electronic address: malshabrawey@gru.edu.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Al-Shabrawey
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism* / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism*; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D051381:Rats; D012160:Retina / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014822:Vitreous Body / Q000378:metabolism; D000089842:Xenotropic and Polytropic Retrovirus Receptor
chemical_list: D055396:Bone Morphogenetic Protein 2; D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; D000089842:Xenotropic and Polytropic Retrovirus Receptor; C000715268:Xpr1 protein, mouse
keywords: BMP 2; Müller cells; VEGF; blood–retinal barrier; diabetic retinopathy; inflammation; leukocyte adhesion; retinal endothelial cells