Molecular pathogenesis of chronic wounds: The role of β-catenin and c-myc in the inhibition of epithelialization and wound healing

Olivera Stojadinovic, Harold Brem, Constantinos Vouthounis, Brian Lee, John Fallon, Michael Stallcup, Ankit Merchant, Robert D. Galiano, Marjana Tomic-Canic

Research output: Contribution to journalArticle

219 Scopus citations

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-catenin 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.

Original languageEnglish (US)
Pages (from-to)59-69
Number of pages11
JournalAmerican Journal of Pathology
Volume167
Issue number1
DOIs
StatePublished - Jul 2005

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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