Collagen XII regulates corneal stromal structure by modulating TGF- β activity

Am J Pathol. 2021 Nov 11:S0002-9440(21)00476-4. doi: 10.1016/j.ajpath.2021.10.014. Online ahead of print.ABSTRACTCollagen XII is a regulator of corneal stroma structure and function. The current study examined the roles of collagen XII in regulating corneal stromal transforming growth factor (TGF)-β activation and latency. Specifically, with the use of conventional collagen XII null mouse model, the roles of collagen XII in the regulation of TGF-β latency and activity in vivo were investigated. Functional quantification of latent TGF-β in stromal matrix was performed by using transformed mink lung reporter cells that produce luciferase as a function of active TGF-β. Col12a1 knock-down with short hairpin RNA (shRNA) was used to test the role of collagen XII in TGF-β activation. We found Col12a1-/- hypertrophic stromas with keratocyte hyperplasia. Increased collagen fibril forward signal was found by second harmonic generation (SHG) microscopy in the absence of collagen XII. Collagen XII regulated mRNA synthesis of Serpine1, Col1a1, and Col5a1 and deposition of collagens in the extracellular matrix. A functional plasminogen activator inhibitor (PAI-1) luciferase assay showed that collagen XII is necessary for latent TGF-β storage in the extracellular matrix and that collagen XII downregulates active TGF-β. Collagen XII dictates stromal structure and function by regulating TGF-β activity. A hypertrophic phenotype in Col12a1-/- corneal tissue can be explained by abnormal ...

Source: The American Journal of Pathology - November 14, 2021 Category: Pathology Authors: Mei Sun Elena Koudouna Devon Cogswell Marcel Y Avila Manuel Koch Edgar M Espana Source Type: research