Bone morphogenetic protein signaling as a key regulator of retinal fibrosis.
9 affiliations
- 1Eye Research Centre, Oakland University William Beaumont School of Medicine, Rochester, MI 48309.
- 2Eye Research Institute, Oakland University, Rochester, MI 48309.
- 3Department of Ophthalmology, King Saud University, Riyadh 11461, Saudi Arabia.
- 4Center for Eye Research and Innovative Diagnostics, Department of Ophthalmology, Oslo University Hospital, Oslo 0450, Norway.
- 5Department of Ophthalmology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0450, Norway.
- 6Department of Ophthalmology, Faculty of Medicine, University of Split, Split 21000, Croatia.
- 7Univerzitet Kliment Ohridski Network, University St. Kliment Ohridski-Bitola, Bitola 7000, Macedonia.
- 8Department of Biologic and Materials Sciences and Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109.
- 9Department of Foundational Medical Studies, Oakland University William Beaumont-School of Medicine, Rochester, MI 48309.
Abstract
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.
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BibTeX
@article{sharma2026bone,
title = {{Bone morphogenetic protein signaling as a key regulator of retinal fibrosis.}},
author = {Sonali Sharma and Gieth Alahdab and Muhammad Nazmul Haque and Ikbal Karkoukli and Alee Assaf and Yuichiro Ishida and Ahmed Abu Elasrar and Mohamed Moustafa and Mohamed Tarek and Xiao Zhang and Kenneth P Mitton and Natasha Josifovska and Goran Petrovski and Hiroki Ueharu and Yuji Mishina and Mohamed Al-Shabrawey},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2603111123},
url = {https://europepmc.org/article/MED/42842407},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Bone morphogenetic protein signaling as a key regulator of retinal fibrosis.
AU - Sonali Sharma
AU - Gieth Alahdab
AU - Muhammad Nazmul Haque
AU - Ikbal Karkoukli
AU - Alee Assaf
AU - Yuichiro Ishida
AU - Ahmed Abu Elasrar
AU - Mohamed Moustafa
AU - Mohamed Tarek
AU - Xiao Zhang
AU - Kenneth P Mitton
AU - Natasha Josifovska
AU - Goran Petrovski
AU - Hiroki Ueharu
AU - Yuji Mishina
AU - Mohamed Al-Shabrawey
PY - 2026
DA - 2026/10/07
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2603111123
UR - https://europepmc.org/article/MED/42842407
AB - 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.
SN - 0027-8424
SN - 1091-6490
ER -