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From the Ronald O. Perelman Department of Dermatology* and the Departments of Microbiology|| and Plastic Surgery,¶ New York University School of Medicine, New York, New York; the Department of Surgery, Wound Healing Program, Columbia University College of Physicians and Surgeons, New York, New York; the Department of Pathology, Mt. Sinai School of Medicine, New York, New York; and the Department of Pathology, University of Southern California, Los Angeles, California
Lack of understanding of the molecular mechanisms and pathogenesis of impaired healing in chronic ulcers is a serious health issue that contributes to excessive limb amputations and mortality. Here we show that ß-catenin and its downstream targets in keratinocytes, c-myc, and keratins K6 and K16, play important roles in the development of chronic wounds. In contrast to normal epidermis, we observed a significant nuclear presence of ß-catenin and elevated c-myc expression at the nonhealing wound edge of chronic ulcers from 10 patients. In vitro studies indicated that stabilization of nuclear ß-catenin inhibited wound healing and keratinocyte migration by blocking epidermal growth factor response, inducing c-myc and repressing the K6/K16 keratins (cytoskeletal components important for migration). The molecular mechanism of K6/K16 repression involved ß-catenin and arginine methyltransferase (CARM-1) acting as co-repressors of glucocorticoid receptor monomers. We conclude that activation of the ß-catenin/c-myc pathway(s) contributes to impaired healing by inhibiting keratinocyte migration and altering their differentiation. The presence of activated ß-cate-nin and c-myc in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.
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