期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 167, 期 1, 页码 59-69出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/S0002-9440(10)62953-7
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资金
- NIAMS NIH HHS [AR45974, R01 AR045974] Funding Source: Medline
- NIDDK NIH HHS [R01 DK043093, DK43093, K08 DK059424] Funding Source: Medline
- NINR NIH HHS [NR08029, R01 NR008029] Funding Source: Medline
- PHS HHS [T3207190] Funding Source: Medline
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 P-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.
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