Glucocorticoid (GC) excess, whether exogenously- or endogenously-derived, induces many adverse effects in skin including thinning, decreased cellularity and reduced collagen synthesis. Consequently, skin exhibits reduced dermal structural integrity, increased atrophy/fragility/bruising and impaired wound healing, effects that perfectly mimic skin ageing. Local GC levels are regulated in a tissue-specific manner by 11β-hydroxysteroid dehydrogenase (11β-HSD) isozymes interconverting active and inactive GC. In murine skin, the NADPH-dependant 11β-HSD1 isozyme predominates, generating corticosterone from inert 11-dehydrocorticosterone (11-DHC). We previously reported increased 11β-HSD1 activity in aged human skin. Our current studies aimed to determine whether this also occurs in mice and contributes to adverse changes in skin integrity during ageing. Using 100 nM radiolabeled 11-DHC, we demonstrated increased 11β-HSD1 activity in shaved dorsal skin explants (~7 mg) from older (9199 weeks, n=5) vs younger (1120 weeks, n=6) mice (fmol/mg/h±S.D., 440±150 vs 260±110 P<0.05). Activity positively correlated with tissue mRNA expression (r2=0.6, P<0.05, n=7), reflecting increased 11β-HSD1 transcription in aged skin. Activity was negligible when co-incubated with an 11β-HSD1-specific inhibitor and absent from in-house generated 11β-HSD1-null (KO) mice. Histological analysis revealed an age-induced dermal atrophy in wild-type mice (n=4), with a sponge-like collagen network, large vacant inter-fibril spaces and diminished structural integrity. Strikingly, these age-related changes were indistinguishable between young and aged KO (n=4). Compared to young mice, aged wild-type mice also displayed reduced dermal cellularity (cells/field of view±S.D. 42±12 vs 71±19, P<0.05) and this was normalized in KO (59±17). Finally, quantitative Masson Trichrome staining indicated 2-fold greater collagen density in aged KO vs wild-type mice (P<0.05, n=4). These studies suggest that adverse structural modifications present in older skin may indeed be as a consequence of increased local GC generation via 11β-HSD1.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.