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Originally published In Press as doi:10.1074/jbc.M107596200 on September 12, 2001

J. Biol. Chem., Vol. 276, Issue 47, 44173-44178, November 23, 2001
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Proteoglycan Expression during Transforming Growth Factor beta -induced Keratocyte-Myofibroblast Transdifferentiation*

James L. FunderburghDagger §, Martha L. FunderburghDagger , Mary M. MannDagger , Lolita Corpuz, and Mary R. Roth

From the Dagger  Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2588 and the  Division of Biology, Kansas State University, Manhattan, Kansas 66506

Keratocytes of the corneal stroma secrete a unique population of proteoglycan molecules considered essential for corneal transparency. In healing corneal wounds, keratocytes exhibit a myofibroblastic phenotype in response to transforming growth factor beta  (TGF-beta ), characterized by expression of alpha -smooth muscle actin. This study examined proteoglycan and collagen expression by keratocytes in vitro during the TGF-beta -induced keratocyte-myofibroblast transition. TGF-beta -treated primary bovine keratocytes developed myofibroblastic features, including actin stress fibers anchored to paxillin-containing focal adhesions, cell-associated fibronectin, alpha 5 integrin, and alpha -smooth muscle actin. Collagen I and III protein and mRNA increased in response to TGF-beta . Secretion of [35S]sulfate-labeled keratan sulfate proteoglycans decreased markedly in response to TGF-beta . Dermatan sulfate proteoglycans, however, increased in size and abundance. Protein and mRNA transcripts for normal stromal proteoglycans (lumican, keratocan, mimecan, and decorin) all decreased in response to TGF-beta , but protein expression and mRNA for biglycan, a proteoglycan present in fibrotic tissue, was markedly up-regulated. These results show that TGF-beta in vitro induces a proteoglycan expression pattern similar to that of corneal scars in vivo. This altered proteoglycan expression occurred coordinately with transdifferentiation of keratocytes to the myofibroblastic phenotype, implicating these cells as the source of fibrotic tissue in nontransparent corneal scars.

* This work was supported by National Institutes of Health Grants EY09368 (to J. L. F.), P30-EY08098 (University of Pittsburgh Department of Ophthalmology Core Grant), and EY00952 (to Gary W. Conrad); Research to Prevent Blindness; and the Eye and Ear Foundation of Pittsburgh.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ A Jules and Doris Stein Research to Prevent Blindness Professor. To whom correspondence should be addressed: Dept. of Ophthalmology, University of Pittsburgh, 1011 Eye and Ear Institute, 203 Lothrop St., Pittsburgh, PA 15213-2588. Tel.: 412-647-3853; Fax: 412-647-5880; E-mail: jlfunder@pitt.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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