11 beta -Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects

Glucocorticoid (GC) excess adversely affects skin integrity, inducing thinning and impaired wound healing. Aged skin, particularly that which has been photo-exposed, shares a similar phenotype. Previously, we demonstrated age-induced expression of the GC-activating enzyme 11 beta -hydroxysteroid dehydrogenase type 1 (11 beta -HSD1) in cultured human dermal fibroblasts (HDFs). Here, we determined 11 beta -HSD1 levels in human skin biopsies from young and older volunteers and examined the aged 11 beta -HSD1 KO mouse skin phenotype. 11 beta -HSD1 activity was elevated in aged human and mouse skin and in PE compared with donor-matched photo-protected human biopsies. Age-induced dermal atrophy with deranged collagen structural organization was prevented in 11 beta -HSD1 KO mice, which also exhibited increased collagen density. We found that treatment of HDFs with physiological concentrations of Cortisol inhibited rate-limiting steps in collagen biosynthesis and processing. Furthermore, topical 11 beta -HSD1 inhibitor treatment accelerated healing of full-thickness mouse dorsal wounds, with improved healing also observed in aged 11 beta -HSD1 KO mice. These findings suggest that elevated 11 beta -HSD1 activity in aging skin leads to increased local GC generation, which may account for adverse changes occurring in the elderly, and 11 beta -HSD1 inhibitors maybe useful in the treatment of age-associated impairments in dermal integrity and wound healing.