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A. I. Jobling, R. Wan, A. Gentle, N. A. McBrien; TGF-Beta as an Intrascleral Mediator of Remodeling During Myopia Development: Regulation of Scleral Proteoglycans. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1735.
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Alterations in collagen and proteoglycan content are important in the scleral remodeling that accompanies myopia development. Previous work has shown that TGF-β1, -β2, and -β3 regulate collagen synthesis by scleral fibroblasts. This study assessed the capacity of TGF-β isoforms to regulate scleral proteoglycan expression, specifically, the regulation of proteoglycan core proteins, glycosaminoglycan (GAG) chain lengths and sulfation.
Tree shrew scleral fibroblasts were exposed to physiologically relevant concentrations of TGF-β isoforms and the incorporation of 35SO4 into proteoglycans monitored (n=3/concentration). Additionally, gene expression of core proteins, aggrecan and decorin, and chondroitin sulfate N-acetylgalactosaminyl transferase-2 (CSGalNAcT-2), an enzyme involved in GAG chain initiation, were assessed using real-time PCR.
TGF-β isoforms were capable of regulating SO4 incorporation into scleral proteoglycans. When isoforms were reduced (in a similar manner to that found during 1 and 5 days myopia development in vivo), there was a 36 ± 3% (p<0.01) and 55 ± 1% (p<0.001) decrease in SO4 incorporation into newly synthesised scleral proteoglycans. The extent of this reduced sulfate incorporation is quantitatively similar to that observed in sclerae of myopic eyes. All TGF-β isoforms negatively regulated the expression of aggrecan and decorin core proteins (~57% and >83% respectively), while the expression of CSGalNAcT-2 increased with increasing TGF-β concentration (>108%). Dose-response curves showed TGF-β3 to be the most potent isoform across all genes, while core proteins were more sensitive (lower EC50) to TGF-β regulation compared to GAG chain initiation (0.13, 0.31, 1.55 ng/ml; TGF-β2 EC50s for decorin, aggrecan, CSGalNAcT-2 respectively).
TGF-β isoforms regulate scleral proteoglycan synthesis at multiple levels including core protein, GAG chain initiation and sulfation. Based on physiological levels of TGF-β in the sclera, TGF-β is likely to mediate its proteoglycan effects through alterations in GAG side chains. As TGF-β regulates scleral collagen and proteoglycan content, this cytokine is likely to be a major intrascleral mediator of remodeling during myopia development.
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