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Bone Morphogenetic Protein-7 Suppresses TGFβ2-Induced Epithelial-Mesenchymal Transition in the Lens: Implications for Cataract Prevention.
- Source :
-
Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2017 Feb 01; Vol. 58 (2), pp. 781-796. - Publication Year :
- 2017
-
Abstract
- Purpose: Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a key pathologic mechanism underlying cataract. Two members of the transforming growth factor-β (TGFβ) superfamily, TGFβ and bone morphogenetic protein-7 (BMP-7) have functionally distinct roles in EMT. While TGFβ is a potent inducer of EMT, BMP-7 counteracts the fibrogenic activity of TGFβ. We examine the modulating effect of BMP-7 on TGFβ-induced EMT in LECs.<br />Methods: Rat lens epithelial explants were treated exogenously with TGFβ2 alone or in combination with BMP-7 for up to 5 days. Expression levels of E-cadherin, β-catenin, α-smooth muscle actin (α-SMA), and phosphorylated downstream Smads were determined using immunofluorescence and Western blotting. Reverse transcriptase quantitative PCR (RT-qPCR) was used to study gene expression levels of EMT markers and downstream BMP target genes, including the Inhibitors of differentiation (Id).<br />Results: Transforming growth factor-β2 induced LECs to transdifferentiate into myofibroblastic cells. Addition of BMP-7 suppressed TGFβ2-induced α-SMA protein levels and mesenchymal gene expression, with retention of E-cadherin and β-catenin expression to the cell membrane. Addition of BMP-7 prevented lens capsular wrinkling and cellular loss associated with TGFβ2-induced EMT over the 5-day treatment period. The inhibitory effect of BMP-7 was accompanied by an early induction of pSmad1/5 and suppression of TGFβ2-induced pSmad2/3. Treatment with TGFβ2 alone suppressed gene expression of Id2/3 and addition of BMP-7 restored Id2/3 expression.<br />Conclusions: Exogenous administration of BMP-7 abrogated TGFβ2-induced EMT in rat lens epithelial explants. Understanding the complex interplay between the TGFβ- and BMP-7-associated Smad signaling pathways and their downstream target genes holds therapeutic promise in cataract prevention.
- Subjects :
- Actins metabolism
Animals
Bone Morphogenetic Protein 7 physiology
Cadherins metabolism
Cataract metabolism
Cell Differentiation drug effects
Cell Membrane metabolism
Epithelial Cells drug effects
Epithelial Cells metabolism
Lens, Crystalline physiology
Mesenchymal Stem Cells metabolism
Models, Animal
Rats
Rats, Inbred LEC
Rats, Wistar
Smad Proteins metabolism
Transforming Growth Factor beta2 antagonists & inhibitors
beta Catenin metabolism
Bone Morphogenetic Protein 7 pharmacology
Epithelial-Mesenchymal Transition drug effects
Lens, Crystalline drug effects
Transforming Growth Factor beta2 pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1552-5783
- Volume :
- 58
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Investigative ophthalmology & visual science
- Publication Type :
- Academic Journal
- Accession number :
- 28152139
- Full Text :
- https://doi.org/10.1167/iovs.16-20611