Fibronectin and β-Catenin Act in a Regulatory Loop in Dermal Fibroblasts to Modulate Cutaneous Healing

beta-Catenin is an important regulator of dermal fibroblasts during cutaneous wound repair. However, the factors that modulate beta-Catenin activity in this process are not completely understood. We investigated the role of the extracellular matrix in regulating beta-Catenin and found an increase in beta-Catenin-mediated Tcf-dependent transcriptional activity in fibroblasts exposed to various extracellular matrix components. This occurs through an integrin-mediated GSK3 beta-dependent pathway. The physiologic role of this mechanism was demonstrated during wound repair in extra domain A-fibronectin-deficient mice, which exhibited decreased beta-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 beta-Catenin signaling. Because fibronectin is a transcriptional target of beta-Catenin, this suggests the existence of a feedback loop between these two molecules that regulates dermal fibroblast cell behavior during wound repair.