Contrasting roles for BMP-4 and ventromorphins (BMP agonists) in TGFβ-induced lens EMT

Exp Eye Res. 2021 May;206:108546. doi: 10.1016/j.exer.2021.108546. Epub 2021 Mar 24.

Abstract

Transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) signaling play opposing roles in epithelial-mesenchymal transition (EMT) of lens epithelial cells, a cellular process integral to the pathogenesis of fibrotic cataract. We previously showed that BMP-7-induced Smad1/5 signaling blocks TGFβ-induced Smad2/3-signaling and EMT in rat lens epithelial cell explants. To further explore the antagonistic role of BMPs on TGFβ-signaling, we tested the capability of BMP-4 or newly described BMP agonists, ventromorphins, in blocking TGFβ-induced lens EMT. Primary rat lens epithelial explants were treated with exogenous TGFβ2 alone, or in combination with BMP-4 or ventromorphins. Treatment with TGFβ2 induced lens epithelial cells to undergo EMT and transdifferentiate into myofibroblastic cells with upregulated α-SMA and nuclear translocation of Smad2/3 immunofluorescence. BMP-4 was able to suppress this EMT without blocking TGFβ2-nuclear translocation of Smad2/3. In contrast, the BMP agonists, ventromorphins, were unable to block TGFβ2-induced EMT, despite a transient and early ability to significantly reduce TGFβ2-induced nuclear translocation of Smad2/3. This intriguing disparity highlights new complexities in the responsiveness of the lens to differing BMP-related signaling. Further research is required to better understand the antagonistic relationship between TGFβ and BMPs in lens EMT leading to cataract.

Keywords: Bone morphogenetic protein (BMP-4); Cataract; Epithelial-mesenchymal transition (EMT); Fibrosis; Myofibroblast; Transforming growth factor-beta (TGFβ); Ventromorphin.

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 4 / agonists*
  • Bone Morphogenetic Protein 4 / metabolism
  • Cataract / drug therapy*
  • Cataract / metabolism
  • Cataract / pathology
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Lens, Crystalline / drug effects*
  • Lens, Crystalline / metabolism
  • Lens, Crystalline / pathology
  • Male
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism

Substances

  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Transforming Growth Factor beta