Crosstalk between transforming growth factor β-2 and Autotaxin in trabecular meshwork and different subtypes of glaucoma

Background: Elevated transforming growth factor (TGF)-beta 2 in aqueous humor (AH) has been suggested to contribute to trabecular meshwork (TM) fibrosis and intraocular pressure (IOP) regulation in primary open-angle glaucoma (POAG), but TGF-beta 2 is downregulated in secondary open-angle glaucoma (SOAG). Because autotaxin (ATX) is upregulated in SOAG, we investigated the relationships and trans-signaling interactions of these mediators. Methods: The level of ATX in AH was determined using a two-site immunoenzymetric assay, and TGF-beta levels were measured using the Bio-Plex Pro TGF-beta Assay. RNA scope was used to assess the expression of ATX and TGF-beta 2 in human's eye specimen. And in vitro studies were performed using hTM cells to explore if trans-signaling of TGF-beta 2 regulates ATX expressions. Results: TGF-beta 2/ATX ratio was significantly high in AH of control or POAG compared with SOAG, and negatively correlated with IOP. RNA scope revelated positive expressions of both TGF-beta 2 and ATX in ciliary body (CB) and TM in control, but ATX expressions was significantly enhanced in SOAG. In hTM cells, ATX expressions were regulated by TGF-beta 2 with concentration-dependent manner. In counter, ATX also induced TGF-beta 1, TGF-beta 2 and TGFBI upregulations and activation of the Smad-sensitive promoter, as well as upregulation of fibrotic markers, and these upregulation was significantly suppressed by both TGF-beta and ATX inhibition. Conclusions: Trans-signaling of TGF-beta 2 regulates ATX expressions and thereby induced upregulations of TGF-beta s or fibrosis of hTM. TGF-beta 2 trans-signaling potently regulate ATX transcription and signaling in hTM cells, which may reflect different profile of these mediators in glaucoma subtypes.

Automated summary

The TGF-β2/ATX ratio was significantly higher in AH of control or POAG compared with SOAG, and negatively correlated with IOP. ATX expressions were regulated by TGF-β2 in hTM cells in a concentration-dependent manner. This study suggests that trans-signaling of TGF-β2 plays a role in regulating ATX expressions and inducing upregulations of TGF-βs or fibrosis in hTM cells, reflecting different profiles of these mediators in glaucoma subtypes.