Estrogen Receptor Is a Novel Therapeutic Target for Photoaging

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) and are ligand-dependent transcription factors that are expressed in skin, and an ER agonist has previously shown efficacy in vivo in models of pain and inflammation. Because ER does not carry the breast and uterine proliferation liabilities of ER , we decided to explore the possibility of using ER as a target for photoaging. We show that ER -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, ER -selective compounds also inhibited COX-2. These activities of ER ligands in skin cells correlated with the expression levels of ER and showed reversal by treatment with a potent synthetic ER antagonist. Furthermore, the pharmacology of ER -selective compound was observed in wild-type but not in skin cells obtained from ER knockout mice. Finally, we demonstrate that a synthetic ER agonist inhibited UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the potential of an ER ligand to regulate multiple pathways underlying the cause of photoaging suggests ER to be a novel therapeutic target for the prevention and treatment of photoaging. Photoaging results from the repetitive exposure of skin to damaging effects of solar UV radiation and is characterized by wrinkles, laxity, dryness, and mottled pigmentation. In recent years, some of the molecular mechanisms underlying the cause of photoaging have been described. The process of photoaging involves three cell types, namely keratinocytes, fibroblasts, and infiltrating neutrophils (Fisher et al., 2002; Rijken et al., 2005; Makrantonaki and Zouboulis, 2007). Within minutes of UVB radiation exposure, epidermal keratinocytes show an increased activation of transcription factors, activator protein 1 (AP-1), and nuclear factorB (NFB), resulting in high expression of matrix metalloproteinases (MMPs) and proinflammatory cytokines (Fisher et al., 1996). These cytokines and a UVA component of the UV radiation in turn activate dermal fibroblasts to secrete MMPs, which damage the collagen component of the dermal extracellular matrix (Fagot et al., 2004). Cytokines and chemotactic factors that are secreted by skin cells also recruit neutrophilic granulocytes to the dermis. These neutrophils further degrade dermal extracellular matrix by secreting MMPs and elastases, thus contributing to UV-mediated dermal collagen and elastin degradation (Rijken et al., 2005). Repetitive UV exposure leads to the accumulation of partially degraded extracellular matrix components in the dermis, resulting in wrinkle appearance. Therefore, a number of pathways and processes involved in photoaging could be targeted by potential therapeu-