ß-Catenin is an important regulator of dermal fibroblasts during cutaneous wound repair. However, the factors that modulate ß-catenin activity in this process are not completely understood. We investigated the role of the extracellular matrix in regulating ß-catenin and found an increase in ß-catenin-mediated Tcf-dependent transcriptional activity in fibroblasts exposed to various extracellular matrix components. This occurs through an integrin-mediated GSK3ß-dependent pathway. The physiologic role of this mechanism was demonstrated during wound repair in extra domain A-fibronectin-deficient mice, which exhibited decreased ß-catenin-mediated signaling during the proliferative phase of healing. Extra domain A-fibronectin-deficient mice have wounds that fail at a lower tensile strength and contain fewer fibroblasts compared with wild type mice. This phenotype was rescued by genetic or pharmacologic activation of ß-catenin signaling. Because fibronectin is a transcriptional target of ß-catenin, this suggests the existence of a feedback loop between these two molecules that regulates dermal fibroblast cell behavior during wound repair.

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