Endocrine Abstracts

Glucocorticoids are highly detrimental to skin integrity and function both when used locally for anti-inflammatory treatments and during conditions of raised systemic concentrations such as Cushing’s syndrome. Many of the adverse effects of glucocorticoids on skin are also symptoms associated with natural intrinsic aging and extrinsic photoaging.

Locally, glucocorticoid availability is regulated independently of circulating levels by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which activates cortisol from cortisone. Surprisingly, studies investigating 11β-HSD1 activity in a dermal context are limited.

We aimed to characterize the localization of 11β-HSD1 in skin and analyze differential expression between old, young, photoprotected and photoexposed dermal fibroblasts.

Immunohistochemistry of full-thickness human skin (Hs) sections (obtained following local ethical approval, n=6) localized 11β-HSD1 to epidermal keratinocytes and dermal fibroblasts. Mouse skin (Ms) sections (n=6) also revealed specific staining in these cell types and in outer root sheath cells. Negligible staining was observed in isotype control-treated sections or those obtained from 11β-HSD1 knock-out (KO) mice (n=6).

Using radioactive substrate conversion assays, 11β-HSD1 oxoreductase activity was identified in skin tissue explants from both species (mouse, 170±30 fmol/mg per h±S.D., n=4; human, 9.6±3.6 fmol/mg per h±S.D., n=15). Activity was undetectable when samples were co-incubated with an 11β-HSD1 inhibitor or when tissue used was obtained from 11β-HSD1 KO mice.

In Hs tissue, there was a positive correlation between 11β-HSD1 oxoreductase activity and age (P<0.05). This was endorsed by real-time PCR data on primary Hs dermal fibroblasts. Fibroblasts derived from both photoexposed and photoprotected sites indicated that 11β-HSD1 expression increased with age (photoprotected, r²=0.49, P<0.05, n=10; photoexposed, r²=0.78, P<0.01, n=10). Additionally, donor-matched photoexposed fibroblasts displayed 2- to 18-fold higher 11β-HSD1 expression than photoprotected fibroblasts (mean ΔC_t 23.1 vs 20.8 respectively, P<0.05, n=7).

We conclude that age- and site-dependant increases in dermal 11β-HSD1, through increasing local GC activation, may play an etiological role in the aging skin phenotype.