Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing.
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 beta-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 beta-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 beta-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 beta-catenin and arginine methyltransferase (CARM-1) acting as co-repressors of glucocorticoid receptor monomers. We conclude that activation of the beta-catenin/c-myc pathway(s) contributes to impaired healing by inhibiting keratinocyte migration and altering their differentiation. The presence of activated beta-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.
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, 550 First Ave., TH100, New York, NY 10016, USA.
Olivera
O
Stojadinovic
Harold
H
Brem
Constantinos
C
Vouthounis
Brian
B
Lee
John
J
Fallon
Michael
M
Stallcup
Ankit
A
Merchant
Robert D
RD
Galiano
Marjana
M
Tomic-Canic
D015415:Biomarkers / Q000378:metabolism*; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000378:metabolism; D004817:Epidermis / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000166:cytology*; D007633:Keratins / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014945:Wound Healing / Q000502:physiology*; D051176:beta Catenin
D015415:Biomarkers; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D051176:beta Catenin; D004815:Epidermal Growth Factor; D007633:Keratins; D008780:Methyltransferases; C077013:PRMT2 protein, human; D011484:Protein-Arginine N-Methyltransferases