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J. Biol. Chem., Vol. 280, Issue 27, 25541-25547, July 8, 2005

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Keratocan, a Cornea-specific Keratan Sulfate Proteoglycan, Is Regulated by Lumican^*

From the ^aDepartment of Ophthalmology, University of Cincinnati, Cincinnati, Ohio 45267-0527, the ^cBascom Palmer Eye Institute and Departments of Ophthalmology, Pharmacology, and Cell Biology, University of Miami School of Medicine, Miami, Florida 33136, the^e Department of Pathology, Anatomy, and Cell Biology Thomas Jefferson University, Philadelphia, Pennsylvania 19107, the^f Department of Ophthalmology, University of Pittsburgh, Pennsylvania 15213, and the ^hDepartment of Ophthalmology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9057

Lumican is an extracellular matrix glycoprotein widely distributed in mammalian connective tissues. Corneal lumican modified with keratan sulfate constitutes one of the major proteoglycans of the stroma. Lumican-null mice exhibit altered collagen fibril organization and loss of corneal transparency. A closely related protein, keratocan, carries the remaining keratan sulfate of the cornea, but keratocan-null mice exhibit a less severe corneal phenotype. In the current study, we examined the effect of lumican overexpression in corneas of wild type mice. These mice showed no alteration in collagen organization or transparency but had increased keratocan expression at both protein and mRNA levels. Corneas of lumican-null mice showed decreased keratocan. This coupling of keratocan expression with lumican also was observed after intrastromal injection of a lumican expression minigene into the corneal stroma of Lum^–/– mice. Small interfering RNA knockdown of lumican in vitro reduced keratocan expression, whereas co-injection of a lumican-expressing minigene with a -galactosidase reporter driven by the keratocan promoter demonstrated an increase of keratocan transcriptional activity in response to lumican expression in Lum^–/– corneas in vivo. These observations demonstrate that lumican has a novel regulatory role in keratocan expression at the transcriptional level. Such results help provide an explanation for the differences in severity of corneal manifestation found in Lum^–/– and Kera^–/– mice. The results also suggest a critical level of small proteoglycans to be essential for collagen organization but that overabundance is not detrimental to extracellular matrix morphogenesis.

Received for publication, January 7, 2005 , and in revised form, April 4, 2005.

^* The studies were in part supported by National Institutes of Health Grants EY11845, EY12486, EY09368, EY13215, EY08098, and EY05129; Research To Prevent Blindness (RPB); and the Ohio Lions Eye Research Foundation. 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.

^b Present address: Dept. of Ophthalmology, Cole Eye Institute Cleveland Clinic Foundation, Cleveland, OH 44195.

^d Recipient of an Olga Weiss Scholarship from RPB.

^g A Julius and Doris Stein RPB Professor of Ophthalmology.

ⁱ Recipients of the RPB Senior Scientific Investigator Award.

^j To whom correspondence should be addressed: Dept. of Ophthalmology, University of Cincinnati, 3223 Eden Ave., Cincinnati, OH 458267-0527. Tel.: 513-558-2802; Fax: 513-558-3108; E-mail: Winston.Kao{at}uc.edu.

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