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Molecular Pathogenesis of Chronic Wounds:The Role of β-Catenin and c- myc in the Inhibition of Epithelialization and Wound Healing

Authors
Journal
American Journal Of Pathology
0002-9440
Publisher
Elsevier
Publication Date
Volume
167
Issue
1
Identifiers
DOI: 10.1016/s0002-9440(10)62953-7
Keywords
  • Cell Injury
  • Repair
  • Aging And Apoptosis
Disciplines
  • Medicine

Abstract

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 β-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 β-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 β-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 β-catenin and arginine methyltransferase (CARM-1) acting as co-repressors of glucocorticoid receptor monomers. We conclude that activation of the β-catenin/c- myc pathway(s) contributes to impaired healing by inhibiting keratinocyte migration and altering their differentiation. The presence of activated β-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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