title: Estradiol protects dermal hyaluronan/versican matrix during photoaging by release of epidermal growth factor from keratinocytes.
abstract: 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.
authors.affiliation: Institut für Pharmakologie and Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Röck
authors.forename: Michael
authors.initials: M
authors.lastname: Meusch
authors.forename: Nikola
authors.initials: N
authors.lastname: Fuchs
authors.forename: Julia
authors.initials: J
authors.lastname: Tigges
authors.forename: Petra
authors.initials: P
authors.lastname: Zipper
authors.forename: Ellen
authors.initials: E
authors.lastname: Fritsche
authors.forename: Jean
authors.initials: J
authors.lastname: Krutmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
authors.forename: Julia
authors.initials: J
authors.lastname: Reifenberger
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects* / Q000528:radiation effects*; D020405:Dermis / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D019899:Paracrine Communication / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects*; D053675:Versicans / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; C508322:VCAN protein, human; C508323:Vcan protein, mouse; D053675:Versicans; D004958:Estradiol; D004815:Epidermal Growth Factor; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C105458:HAS3 protein, human; C491356:Has3 protein, mouse; D000076002:Hyaluronan Synthases