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J. Biol. Chem., Vol. 279, Issue 18, 18121-18126, April 30, 2004

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Isoform-specific Changes in Scleral Transforming Growth Factor- Expression and the Regulation of Collagen Synthesis during Myopia Progression^*

Andrew I. Jobling, Martin Nguyen, Alex Gentle, and Neville A. McBrien

From the Department of Optometry and Vision Sciences, The University of Melbourne, Victoria 3010, Australia

The development of high myopia is associated with altered scleral extracellular matrix biochemistry. Previous studies highlight the importance of collagen turnover in this process, yet it is unclear which factors control scleral remodeling. This study used a mammalian model of myopia to investigate the capacity of TGF (transforming growth factor)-1, -2, and -3 to influence scleral remodeling in myopia. RT-PCR confirmed the presence of all mammalian TGF- isoforms in scleral tissue and scleral fibroblasts. Myopia was experimentally induced via monocular deprivation of pattern vision, and animals were allocated to two groups depending on the duration of treatment (1 or 5 days). Down-regulation of each isoform was apparent after only 1 day of myopia development (TGF-1, –32%; TGF-2, –27%; TGF-3, –42%). Whereas the decrease in TGF-1 and -3 expression was relatively constant between the two time points, differential down-regulation of TGF-2 was found between days 1 (–27%) and 5 (–50%). In vitro experiments, using primary scleral fibroblasts, demonstrated the capacity of all isoforms to increase collagen production in a dose-dependent manner. Changes in TGF- levels, which mimicked those during myopia induction, caused an 15% reduction in collagen synthesis, which is qualitatively similar to those previously reported in vivo. These data represent the first demonstration of TGF-3 expression in the sclera and implicate all three TGF- isoforms in the control of scleral remodeling during myopia development. In addition, the early alterations in TGF- expression levels may reflect a role for these cytokines in mediating the retinoscleral signal that controls myopic eye growth.

Received for publication, January 14, 2004

^* This work was supported by Grants 145700 and 251557 from the National Health and Medical Research Council of Australia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 61-03-8344-7001; Fax: 61-03-9349-7474; E-mail: n.mcbrien{at}optometry.unimelb.edu.au.

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