Estradiol Protects Dermal Hyaluronan/Versican Matrix during Photoaging by Release of Epidermal Growth Factor from Keratinocytes

Hyaluronan (HA) and versican are key components of the dermis and are responsive to ultraviolet (UV) B-induced remodeling. The aim of this study was to explore the molecular mechanisms mediating the effects of estrogen (E-2) on HA-rich extracellular matrix during photoaging. Hairless skh-1 mice were irradiated with UVB (three times, 1 minimal erythema dose (80 mJ/cm(2)), weekly) for 10 weeks, and endogenous sex hormone production was abrogated by ovariectomy. Subcutaneous substitution of E-2 by means of controlled-release pellets caused a strong increase in the dermal HA content in both irradiated and nonirradiated skin. The increase in dermal HA correlated with induction of HA synthase HAS3 by E-2. Expression of splice variant 2 of the HA-binding proteoglycan versican was also increased by E-2. In search of candidate mediators of these effects, it was found that E-2 strongly induced the expression of epidermal growth factor (EGF) in UVB-irradiated epidermis in vivo and in keratinocytes in vitro. EGF in turn up-regulated the expression of HAS3 and versican V2 in dermal fibroblasts. HAS3 knockdown by shRNA caused inhibition of fibroblast proliferation. Furthermore, HAS3 and versican V2 induction by E-2 correlated positively with proliferation in vivo. In addition, the accumulation of inflammatory macrophages, expression of inducible cyclooxygenase 2, as well as proinflammatory monocyte chemotactic protein 1 were decreased in response to E-2 in the dermis. Collectively, these data suggest that E-2 treatment increases the amount of dermal HA and versican V2 via paracrine release of EGF, which may be implicated in the pro-proliferative and anti-inflammatory effects of E-2 during photoaging.