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Inhibition of Hyaluronan Synthase 2 Reduces the Abnormal Migration Rate of Keloid Keratinocytes

Supp, Dorothy M. PhD*†; Hahn, Jennifer M. BS*; McFarland, Kevin L. MS*; Glaser, Kathryn BA*

doi: 10.1097/BCR.0b013e3182a2a9dd
Original Articles: 2013 ABA Papers

Keloids are fibroproliferative scars that spread beyond the original wound boundary and are very resistant to treatment. Development of highly effective therapies requires a comprehensive understanding of the mechanisms regulating keloid formation. Previous studies indicated that keloid keratinocytes have abnormal expression of genes involved in differentiation and adhesion, and increased migration rates. The objective of the current study was to better understand the role of hyaluronan synthase 2 (HAS2) in keloid keratinocyte migration and gene expression. Keratinocytes were isolated from keloid scars and normal skin. Migration rates of keloid keratinocytes were quantified using an in vitro scratch assay. Expression levels of HAS2, related HAS1, and HAS3 genes, and genes aberrantly expressed in keloid keratinocytes, were quantified using real-time polymerase chain reaction. Treatment with 4-methylumbelliferone (4MU) was used to inhibit hyaluronic acid synthesis. The expression of HAS2 was significantly increased in keloid vs normal keratinocytes. Treatment with 4MU caused a dose-dependent reduction in keloid keratinocyte migration and HAS2 expression; HAS3 expression was moderately inhibited by 4MU and HAS1 was not expressed. Keloid keratinocytes displayed a motile phenotype in vitro, including loose colonies and widely separated refractile cells; this phenotype was normalized by 4MU. Further, 4MU altered gene expression in keloid keratinocytes. The results suggest that HAS2 overexpression contributes to increased migration and altered gene expression in keloid keratinocytes. Abnormal keratinocyte migration may contribute to the overhealing of keloid scars beyond the original wound boundaries. Therefore, inhibition of HAS2 expression using 4MU may represent a novel strategy for treatment of keloid scarring.

From the *Department of Research, Shriners Hospitals for Children—Cincinnati, Ohio; and Department of Surgery, College of Medicine, University of Cincinnati, Ohio.

This work was supported by Medical Research Grant #86200 from the Shriners Hospitals for Children.

Address correspondence to Dorothy M. Supp, PhD, Shriners Hospitals for Children—Cincinnati, 3229 Burnet Avenue, Cincinnati, Ohio, 45229.

© 2014 The American Burn Association