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

O Stojadinovic, H Brem, C Vouthounis, B Lee… - The American journal of …, 2005 - Elsevier
O Stojadinovic, H Brem, C Vouthounis, B Lee, J Fallon, M Stallcup, A Merchant, RD Galiano…
The American journal of pathology, 2005Elsevier
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 …
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.
Elsevier