Characterization of mechanisms regulating scleral extracellular matrix remodeling to promote myopia development.

摘要

Myopia (nearsightedness) is commonly the result of excessive elongation of the vitreous chamber that is facilitated by the remodeling of the scleral extracellular matrix at the posterior pole of the eye. Corrective lenses and laser-assisted surgery are techniques used to correct myopia; however, in some cases, the degree of myopia continues to progress overtime placing the individual at an increased risk for retinal detachment and blindness. Interestingly, myopia onset has been strongly linked to both genetics and the environment, but the molecular mechanisms by which myopia develops are still not well understood. Therefore, it is important to elucidate the mechanism(s) regulating myopia development in an attempt to provide a therapeutic approach to prevent or slow the progression of myopia. Our lab is interested in understanding the involvement of the choroid in promoting the remodeling of the scleral extracellular matrix. Microarray analysis was utilized to identify gene expression differences in the choroid/RPE tissue layer of the eyes of juvenile marmosets ( Callithrix jacchus) undergoing plus (relative hyperopia) and minus (relative myopia) lens-induced refractive errors. We found that transforming growth factor beta-induced gene (TGFBI/BIGH3) was significantly upregulated in the choroid/RPE's of marmoset eyes undergoing minus lens-treatment (relative myopia). The protein encoded by TGFBI, TGFBIp (Beta ig-h3), was identified by western blot analysis in marmoset and human choroid/RPE, sclera, cornea, but not retina. We further studied the role of the extracellular matrix secreted protein, TGFBIp, in human scleral fibroblast binding and attachment. TGFBIp was shown to inhibit human scleral fibroblast attachment to collagen type I which may be critical for promoting the remodeling of the scleral extracellular matrix. However, the function of TGFBIp has been controversial with some groups reporting it to promote adhesion, whereas others (including our lab) report that it negatively regulates adhesion. We have used in vitro cell based functional assays, and identified that TGFBIp inhibits human scleral fibroblast, but not foreskin fibroblast or cornea stromal fibroblast attachment to collagen type I, suggesting its specific nature among different cell types. Further, biochemical data indicated that TGFBIp binds to the surface of scleral fibroblasts via alphavbeta3 and alphavbeta5 integrin cell surface receptors. Together, these data suggest that TGFBIp may promote scleral extracellular matrix remodeling events to occur by altering the biomechanical properties of the sclera by promoting cell detachment; thereby increasing the distensibility of the sclera.