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Weiming Mao, Anirudh Sethi, Robert J. Wordinger, Abbot F. Clark; Crosstalk Between The Wnt And Tgf-beta Pathways In The Trabecular Meshwork. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2747. doi: https://doi.org/.
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Glaucoma is a leading cause of visual impairment and blindness worldwide. The primary risk factor of the development and progression of glaucoma is elevated intraocular pressure (IOP), which results from damage to the trabecular meshwork (TM). Emerging evidence has shown that the Wnt and TGF-beta signaling pathways play important roles in TM homeostasis and IOP regulation. The purpose of this study is to determine whether there is a crosstalk between the two glaucoma-associated cell signaling pathways in the TM.
Human TM (HTM) cells were transfected with luciferase reporter vectors for the Wnt pathway or TGF-beta pathways. Cells were treated with or without Wnt3a (100ng/ml), SFRP1 (2ug/ml), or TGF-beta2 5ng/ml) for 16 to 24 hours before assay development. RNA or nuclear and cytosolic proteins from HTM cells treated with or without Wnt3a or TGF-beta2 for 4 hours were used for PCR array or western immunoblotting, respectively.
We found that TGF-beta 2 inhibited the basal signaling activity of the Wnt pathway, while SFRP1 inhibited the basal signaling activity of the TGF-beta pathway in HTM cells by luciferase assays (n=3, p<0.05). In addition, western immunoblotting showed that Wnt3a induced translocation of phosphorylated SMADs-2,3 and 4 into the nucleus. A similar nuclear translocation of beta-catenin was also induced by TGF-beta2. SMADs-2, 3, and 4 are the key mediators for the TGF-beta pathway, while beta-catenin is essential for the activation of the canonical Wnt signaling pathway. PCR array studies showed that a number of cell signaling pathway components of the Wnt or TGF-beta pathways could be regulated by the manipulating the activity of the other pathway.
There is crosstalk between the Wnt and TGF-beta pathways in the trabecular meshwork. Additional studies will further characterize these pathway interactions and their role(s) in regulating IOP.
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