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.
Stojadinovic
Olivera
O
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, 550 First Ave., TH100, New York, NY 10016, USA.
Brem
Harold
H
Vouthounis
Constantinos
C
Lee
Brian
B
Fallon
John
J
Stallcup
Michael
M
Merchant
Ankit
A
Galiano
Robert D
RD
Tomic-Canic
Marjana
M
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