Ezrin expression and activation in hypertrophic and keloid scar

Purpose: Hypertrophic and keloid scar formation occur as a result of aberrant wound healing. Ezrin, a member of the ezrin, radixin, and moesin (ERM) family of proteins, acts as a regulator of cell-to-cell interactions and extracellular matrix (ECM) density and stiffness in tissue remodeling during wound healing. In this study, we examined the expression and activation of ezrin in normal skin and hypertrophic and keloid scars. Methods: Our study consisted of two parts. First, we evaluated the expression and activation of immunoreactive ezrin during the wound healing process in mouse skin. Immunohistochemistry and H-testing were employed. After proving the presence and activation of ezrin in healing skin we compared ezrin expression and activation in normal skin, hypertrophic scar and keloid scars from women undergoing unrelated surgery. Localization and relative amounts of ezrin and phosphorylated ezrin (activated, p-ezrin) protein were examined by immunohistochemistry, H-testing and western blotting. Results: Expression and activation of ezrin was confirmed and shown to increase during wound healing in mouse skin. In women, expression of ezrin and p-ezrin were increased in both hypertrophic and keloid scars relative to normal skin. While both ezrin and p-ezrin were expressed primarily in the epidermal layer, keloids had both increased numbers of lymphocytes and overexpression of activated ezrin in their overgrown dermis. Conclusions: The is the first report of ezrin in scar tissues. Ezrin is an important structural protein in normal and abnormal wound healing. Activated ezrin plays a major role in the formation and integrity of intercellular junctions between epithelial cells. Hypertrophic scar usually forms in areas of tension on the healing wound. The remarkable amounts of ezrin and activated ezrin in the basal epithelium of hypertrophic scar could reflect their roles in the widened areas of epithelium that are characteristic of this type of healing abnormality. Keloid scar is characterized by a thin, corrugated epidermis with few rete pegs. There is no papillary layer of dermis, just an overabundance of loose collagenous ropes beneath the epithelium. The presence of lymphocytes in the dermis is characteristic of bland inflammation which includes expression of cytokines and growth factors that could induce and activate ezrin and determine the disposition of the collagen fibers. Since these inflammatory factors and proteins, as well as ezrin are all regulated by estrogen, these findings could help to explain the salutary effect of the estrogen antagonist tamoxifen on keloids.