Bone Morphogenetic Protein-7 Suppresses TGFß2-Induced Epithelial-Mesenchymal Transition in the Lens: Implications for Cataract Prevention.

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-ß (TGFß) superfamily, TGFß and bone morphogenetic protein-7 (BMP-7) have functionally distinct roles in EMT. While TGFß is a potent inducer of EMT, BMP-7 counteracts the fibrogenic activity of TGFß. We examine the modulating effect of BMP-7 on TGFß-induced EMT in LECs. Methods: Rat lens epithelial explants were treated exogenously with TGFß2 alone or in combination with BMP-7 for up to 5 days. Expression levels of E-cadherin, ß-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). Results: Transforming growth factor-ß2 induced LECs to transdifferentiate into myofibroblastic cells. Addition of BMP-7 suppressed TGFß2-induced α-SMA protein levels and mesenchymal gene expression, with retention of E-cadherin and ß-catenin expression to the cell membrane. Addition of BMP-7 prevented lens capsular wrinkling and cellular loss associated with TGFß2-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 TGFß2-induced pSmad2/3. Treatment with TGFß2 alone suppressed gene expression of Id2/3 and addition of BMP-7 restored Id2/3 expression. Conclusions: Exogenous administration of BMP-7 abrogated TGFß2-induced EMT in rat lens epithelial explants. Understanding the complex interplay between the TGFß- and BMP-7-associated Smad signaling pathways and their downstream target genes holds therapeutic promise in cataract prevention.