Aqueous Humor TGF-β2 and Its Association With Intraocular Pressure in a Naturally Occurring Large Animal Model of Glaucoma

Abstract

Purpose Transforming growth factor (TGF)-β2 has been widely implicated in human glaucoma pathology. The purpose of this study was to determine the source of TGF-β2 in aqueous humor (AH) and its relationship with intraocular pressure (IOP) in an inherited large animal model of glaucoma. Methods Sixty-six glaucomatous cats homozygous for LTBP2 mutation, and 42 normal cats were studied. IOP was measured weekly by rebound tonometry. AH was collected by anterior chamber paracentesis from each eye under general anesthesia, and serum samples collected from venous blood concurrently. Concentrations of total, active and latent TGF-β2 in AH and serum samples were measured by quantitative sandwich immunoassay. For comparisons between groups, unpaired t -test or Mann Whitney test were used, with P < 0.05 considered significant. The relationships between TGF-β2 concentrations and IOP values were examined by Pearson's correlation coefficient and generalized estimating equation. Results IOP and AH TGF-β2 concentrations were significantly higher in glaucomatous than in normal cats. AH TGF-β2 showed a significant, robust positive correlation with IOP in glaucomatous cats ( r = 0.83, R 2 = 0.70, P < 0.0001). Serum TGF-β2 did not correlate with AH TGF-β2 and was not significantly different between groups. TGF-β2 mRNA and protein expression were significantly increased in local ocular tissues in glaucomatous cats. Conclusions Enhanced, local ocular production of TGF-β2 with a robust positive association with IOP was identified in this spontaneous feline glaucoma model, providing a foundation for preclinical testing of novel therapeutics to limit disease-associated AH TGF-β2 elevation and signaling in glaucoma.

Modeling the critical MCOR-causing deletion in mouse unveils aberrantSox21expression in developing and adult iris and ciliary body, and implicatesTgfβ2in MCOR-associated glaucoma and myopia

“…However, studies have demonstrated that cells from the trabecular meshwork, through which aqueous humor is drained out at the iridocorneal angle, express an active TGF receptor complex and respond to exogenous TGFB2 (Medina-Ortiz et al 2013;Montecchi-Palmer et al 2017). This has been reported to result in increased synthesis of extracellular matrix proteins (ECM), accumulation of which increases resistance to aqueous outflow, leading to elevated intraocular pressure and glaucoma in both human and mouse (Zeimer et al 1998;Munemasa and Kitaoka 2012;Prendes et al 2013;Oikawa et al 2023). This knowledge, combined with (i) the histopathologic examination of trabecular meshwork (TM) biopsies from two microcoric brothers with elevated IOP, that revealed ECM accumulation (Tawara et al 2005), and (ii) an elevated concentration of TGFB2 in the aqueous humor of an individual with MCOR, implies that glaucoma associated with MCOR may be initiated by SOX21.…”

“…39,40 This has been reported to result in increased synthesis of extracellular matrix proteins (ECM), accumulation of which increases resistance to aqueous outflow, leading to elevated IOP and GLC in human, primates, cats and mouse. 9–12,41…”

“…39,40 This has been reported to result in increased synthesis of extracellular matrix proteins (ECM), accumulation of which increases resistance to aqueous outflow, leading to elevated IOP and GLC in human, primates, cats and mouse. [9][10][11][12]41 This knowledge, combined with (i) the histopathologic examination of TM biopsies from two microcoric brothers with elevated IOP, that revealed ECM accumulation, 42 and (ii) an elevated concentration of TGFB2 in the AH of an individual with MCOR, implies that GLC associated with MCOR may be initiated by SOX21. The strength of this inference is heightened by our findings, which provide evidence of ectopic Sox21 expression in the CBwhere the AH is produced-specifically in the non-pigmented PEL.…”

“…1 Our investigation into the Wnt/β-catenin pathway highlights the substantial elevation of Wnt2b expression (MIM*601968; FC= 3.57, p < 0.01 Figure S4A and S4C), a gene crucial for specifying iris progenitor cells towards a myoepithelial fate. 1 In the context of BMP and TGFB signaling pathways, we observed upregulation in Bmp7 (MIM112267; 1.92, p<0.05 Figure S4B and S4C), implicated in iris smooth muscle generation, 1 and Tgfβ2 (MIM*190220; FC 1.6, p<0.01), known for its role in iris and ciliary body specification, as well as in glaucoma [9][10][11][12] (Figure S4B and S4C), and potentially associated with high myopia. [13][14] Furthermore, we observed an enrichment of genes associated with the regulation of smooth muscle cell proliferation, though with a lower significance ranking (top 45; Figure 5).…”

“…Additionally, we identify the transforming growth factor, beta (TGFB)-2 encoding gene (Tgfβ2; MIM*190220) as a SOX21 target gene and TGFB2 accumulation in the AH of a MCOR-affected subject. This accumulation, known for its role in GLC [9][10][11][12] and potential impact on axial myopia, 13,14 underscores the significance of SOX21-TGFB2 signaling in these ocular anomalies and iris development. Insights from MCOR studies may offer therapeutic avenues for individuals with this condition, as well as those with primary open-angle glaucoma (POAG) and high myopia, affecting millions.…”