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Bone Morphogenetic Protein-7 Suppresses TGFβ2-Induced Epithelial-Mesenchymal Transition in the Lens: Implications for
Daisy Y Shu1, Magdalena C Wojciechowski2, Frank J Lovicu1
1Discipline of Anatomy and Histology, Bosch Institute, University of Sydney, New South Wales, Australia 2Save Sight Institute, University of Sydney, New South Wales, Australia.
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.
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).
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.
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.
Insights
Bone morphogenetic protein-7 (BMP-7) prevents cataract formation by inhibiting transforming growth factor-β2 (TGFβ2)-induced epithelial-mesenchymal transition (EMT) in lens epithelial cells. BMP-7 counteracts TGFβ2
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Biology
Background:
- Epithelial-mesenchymal transition (EMT) in lens epithelial cells (LECs) is a critical process in cataract development.
- Transforming growth factor-β (TGFβ) and bone morphogenetic protein-7 (BMP-7) have opposing roles in EMT.
- TGFβ induces EMT, while BMP-7 inhibits this fibrogenic activity.
Purpose of the Study:
- To investigate the effect of BMP-7 on TGFβ-induced EMT in LECs.
- To elucidate the molecular mechanisms underlying BMP-7's modulation of TGFβ signaling in the context of cataractogenesis.
Main Methods:
- Rat lens epithelial explants were treated with TGFβ2 and BMP-7.
- Immunofluorescence and Western blotting were used to assess protein expression (E-cadherin, β-catenin, α-SMA, phosphorylated Smads).
- RT-qPCR analyzed gene expression of EMT markers and BMP target genes (Id proteins).
Main Results:
- TGFβ2 induced LECs to transdifferentiate into myofibroblasts, characterized by increased α-SMA and loss of E-cadherin/β-catenin.
- BMP-7 suppressed TGFβ2-induced α-SMA and mesenchymal gene expression, maintaining cell-cell junctions.
- BMP-7 inhibited lens capsular wrinkling and cellular loss, induced early pSmad1/5, suppressed pSmad2/3, and restored Id2/3 expression.
Conclusions:
- Exogenous BMP-7 effectively blocked TGFβ2-induced EMT in rat lens explants.
- Understanding the cross-talk between TGFβ and BMP-7 Smad pathways offers potential therapeutic strategies for cataract prevention.
