May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
TGF-Beta as an Intrascleral Mediator of Remodeling During Myopia Development: Regulation of Scleral Proteoglycans
Author Affiliations & Notes
  • A. I. Jobling
    Optometry & Vision Sciences, University of Melbourne, Melbourne, Australia
  • R. Wan
    Optometry & Vision Sciences, University of Melbourne, Melbourne, Australia
  • A. Gentle
    Optometry & Vision Sciences, University of Melbourne, Melbourne, Australia
  • N. A. McBrien
    Optometry & Vision Sciences, University of Melbourne, Melbourne, Australia
  • Footnotes
    Commercial Relationships  A.I. Jobling, None; R. Wan, None; A. Gentle, None; N.A. McBrien, None.
  • Footnotes
    Support  NH&MRC#454602
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 1735. doi:https://doi.org/
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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. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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).

Conclusions: : 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.

Keywords: myopia • sclera • cytokines/chemokines 
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