TGF-beta Signal Transduction in Fibrosis Associated with Open Angle Glaucoma

Michelle Won

 Introduction. Primary open-angle glaucoma (POAG) affects 70 million patients worldwide and is the second leading cause of blindness. POAG is primarily characterized by disruption of aqueous outflow, leading to high interocular pressure (IOP), causing progressive degeneration of retinal ganglion cells1.The TGF-b family of cytokines is known to increase fibrosis and deposition of ECM proteins from various fibrotic cells, including trabecular meshwork cells of the eye, leading to blocked aqueous outflow and increased IOP1. Greater understanding of TGF-B signaling in trabecular meshwork cells suggests a target for therapy to decrease fibrosis and relieve aqueous humor obstruction.  Methods. Various cell types were introduced to TGF-B, and changes in fibrosis, collagen deposition, and production of ECM proteins were observed by immunofluorescence staining and PCR2. Additionally, Smad2 and Smad2/3, key proteins in the TGF-B canonical pathway, were regulated to observe changes in fibrosis and ECM deposition in mice cardiac fibroblasts3. Furthermore, PTEN, another important signaling molecule in the TGF-B pathway known to modulate Smad2/3 activity, was inhibited in human trabecular meshwork cells to observe effects on fibrosis and ECM deposition4. Results. Introduction of TGF-b2 resulted in increased fibrosis, infiltration of leukocytes, and increased collagen fibers, as well as increased deposition of ECM proteins such as E-cadherin, vimentin, fibronectin, collagen I, albumin, MMP2, and MMP9 in mice mammary cells and bovine epithelial cells compared to controls2. Deletion of Smad3 and Smad2/3 lead to significant reduction of fibrosis and reduced levels of Collagen1a1 and Collagen3a1 in mice cardiac fibroblasts compared to non-knockout mice3. Inhibition of PTEN with VO-OHpic lead to increased collagen production in human trabecular meshwork cells4. Conclusions. Because the TGF-B/Smad signaling pathway has been confirmed to play a role in fibrosis and ECM deposition, it is important to consider regulation of this pathway in therapy for POAG. However, the ECM goes through a dynamic remodeling process that is useful for development, wound healing, and normal tissue homeostasis. Thus, only targeting TGFB or Smad 2/3 molecules may lead to complications in the maintenance of ECM, making it crucial to target a mechanism that will regulate TGF-B activity so that fibrosis is prevented, without compromising its normal homeostatic role in ECM remodeling4. The research suggest that PTEN regulators will have tighter control on Smad2/3 signaling and regulation of ECM deposition, and various pharmacological agents have been proposed to target PTEN activation for future POAG therapy.

 

  1. Pervan, C. (2016). Smad-independent TGF-β2 signaling pathways in human trabecular meshwork cells. Experimental Eye Research, 158, pp.137-145.
  2. Chen, Q., Yang, W., Wang, X., Li, X., Qi, S., Zhang, Y. and Gao, M. (2017). TGF-β1 Induces EMT in Bovine Mammary Epithelial Cells Through the TGFβ1/Smad Signaling Pathway. Cellular Physiology and Biochemistry, 43(1), pp.82-93.
  3. Khalil, H., Kanisicak, O., Prasad, V., Correll, R., Fu, X., Schips, T., Vagnozzi, R., Liu, R., Huynh, T., Lee, S., Karch, J. and Molkentin, J. (2017). Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis. Journal of Clinical Investigation, 127(10), pp.3770-3783.
  4. Tellios, N., Belrose, J., Tokarewicz, A., Hutnik, C., Liu, H., Leask, A., Motolko, M., Iijima, M. and Parapuram, S. (2017). TGF-β induces phosphorylation of phosphatase and tensin homolog: implications for fibrosis of the trabecular meshwork tissue in glaucoma. Scientific Reports, 7(1).