Fibrotic Response of Human Trabecular Meshwork Cells to Transforming Growth Factor-Beta 3 and Autotaxin in Aqueous Humor

This study examines the potential role of transforming growth factor-beta 3 (TGF-beta 3) on the fibrotic response of cultured human trabecular meshwork (HTM) cells. The relationships and trans-signaling interactions between TGF-beta 3 and autotaxin (ATX) in HTM cells were also examined. The levels of TGF-beta and ATX in the aqueous humor (AH) of patients were measured by an immunoenzymetric assay. The TGF-beta 3-induced expression of the fibrogenic markers, fibronectin, collagen type I alpha 1 chain, and alpha-smooth muscle actin, and ATX were examined by quantitative real-time PCR, Western blotting, and immunocytochemistry, and the trans-signaling regulatory effect of TGF-beta 3 on ATX expression was also evaluated. In HTM cells, the significant upregulation of ATX was induced by TGF-beta 3 at a concentration of 0.1 ng/mL, corresponding to the physiological concentration in the AH of patients with exfoliative glaucoma (XFG). However, higher concentrations of TGF-beta 3 significantly suppressed ATX expression. TGF-beta 3 regulated ATX transcription and signaling in HTM cells, inducing the upregulation of fibrogenic proteins in a dose-dependent manner. Trans-signaling of TGF-beta 3 regulated ATX transcription, protein expression, and signaling, and was thereby suggested to induce fibrosis of the trabecular meshwork. Modulation of trans-signaling between TGF-beta 3 and ATX may be key to elucidate the pathology of XFG, and for the development of novel treatment modalities.