Abstract

One of the many harmful factors faced by the skin is solar UV radiation, which damages skin by inducing chronic low-grade inflammation through increased expression of proinflammatory cytokines, metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Estrogen receptors (ERs) α and β are ligand-dependent transcription factors that are expressed in skin, and an ERβ agonist has previously shown efficacy in vivo in models of pain and inflammation. Because ERβ does not carry the breast and uterine proliferation liabilities of ERα, we decided to explore the possibility of using ERβ as a target for photoaging. We show that ERβ-selective compounds suppressed the expression of cytokines and MMPs in activated keratinocytes and fibroblast-based in vitro models of photoaging. Furthermore, in activated dermal fibroblasts, ERβ-selective compounds also inhibited COX-2. These activities of ERβ ligands in skin cells correlated with the expression levels of ERβ and showed reversal by treatment with a potent synthetic ER antagonist. Furthermore, the pharmacology of ERβ-selective compound was observed in wild-type but not in skin cells obtained from ERβ knockout mice. Finally, we demonstrate that a synthetic ERβ agonist inhibited UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the potential of an ERβ ligand to regulate multiple pathways underlying the cause of photoaging suggests ERβ to be a novel therapeutic target for the prevention and treatment of photoaging.