Bone morphogenetic protein signaling as a key regulator of retinal fibrosis

Retinal fibrosis is a blinding complication of proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), age-related macular degeneration (AMD) and idiopathic epiretinal membrane (iERM), yet effective therapies remain lacking. The purpose of this study was to investigate the role of BMP2 and BMP4 (BMP2/4)-activin receptor-like kinase (ALK) signaling in retinal fibrosis. BMP2 was detected in the vitreous of PDR, PVR, and rhegmatogenous retinal detachment (RRD) samples at concentration of 70, 180, and 85 pg/mL respectively, whereas it was present only at trace levels or was undetectable in the vitreous of macular hole and idiopathic ERM samples (~0.1 pg/mL). PDR, PVR, and idiopathic ERMs exhibited strong immunoreactivity for BMP2, BMP4, ALK3 (Bmpr1a), pSMAD1/5/9, and pSMAD4. Formation of preretinal fibronectin-containing membranes resulted from intravitreal injection of wild-type mice with BMP2 and similar membranes formed in mice expressing constitutively active ALK3 (caBmpr1a). The presence of preretinal membrane in caBmpr1a was confirmed by optical coherence tomography. The limited hyperoxia-induced proliferative retinopathy (LIHPR) model demonstrated a progressive increase in the retinal expression of BMP2 and BMP4and development of preretinal membrane. Administration of BMP/ALK inhibitor LDN193189 induced regression of the preretinal membrane in LHIPR. BMP2 and BMP4 induced a significant increase in the expression of Glial Fibrillary Acidic Protein (GFAP), fibronectin, and collagen-VI in cultured rat Muller glial cells, and increased fibronectin was reversed by BMP/ALK inhibition. BMP2 also significantly upregulated fibronectin and activated matrix metalloproteinase-2 in human retinal endothelial cells. These findings support BMP2/4-ALK signaling as a potential mediator and therapeutic target in retinal fibrosis.