School of Medical Sciences, The University of Sydney, NSW, Australia; Save Sight Institute, The University of Sydney, NSW, Australia.
School of Medical Sciences, The University of Sydney, NSW, Australia.
Exp Eye Res. 2021 May;206:108546. doi: 10.1016/j.exer.2021.108546. Epub 2021 Mar 24.
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.
转化生长因子 β（TGFβ）和骨形态发生蛋白（BMP）信号在晶状体上皮细胞的上皮-间充质转化（EMT）中发挥相反的作用，这是纤维性白内障发病机制中不可或缺的细胞过程。我们之前表明，BMP-7 诱导的 Smad1/5 信号阻断 TGFβ 诱导的 Smad2/3 信号和大鼠晶状体上皮细胞外植体中的 EMT。为了进一步探索 BMPs 对 TGFβ 信号的拮抗作用，我们测试了 BMP-4 或新描述的 BMP 激动剂 ventromorphin 阻断 TGFβ 诱导的晶状体 EMT 的能力。原代大鼠晶状体上皮外植体单独用外源性 TGFβ2 处理，或与 BMP-4 或 ventromorphin 联合处理。TGFβ2 处理诱导晶状体上皮细胞发生 EMT，并向具有上调的α-SMA 和 Smad2/3 免疫荧光核转位的肌成纤维细胞转化。BMP-4 能够抑制这种 EMT，而不阻断 Smad2/3 的 TGFβ2 核转位。相比之下，BMP 激动剂 ventromorphin 尽管能够在早期短暂地显著减少 TGFβ2 诱导的 Smad2/3 核转位，但不能阻断 TGFβ2 诱导的 EMT。这种有趣的差异突出了晶状体对不同 BMP 相关信号的反应性的新复杂性。需要进一步研究以更好地了解 TGFβ 和 BMPs 在晶状体 EMT 导致白内障中的拮抗关系。
