11[Beta]-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects

• Published in: The Journal of clinical investigation 2013-07, Vol.123 (7), p.3051
• Main Authors: Tiganescu, Ana, Tahrani, Abd A, Morgan, Stuart A, Otranto, Marcela, Desmoulière, Alexis, Abrahams, Lianne, Hassan-Smith, Zaki, Walker, Elizabeth A, Rabbitt, Elizabeth H, Cooper, Mark S, Amrein, Kurt, Lavery, Gareth G, Stewart, Paul M
• Format: Article
• Language: English
• Subjects: Age; Aging; Biomedical research; Biosynthesis; Collagen; Dehydrogenases; Gene expression; Rodents; Skin; Software; Wound healing
• ISSN: 0021-9738; 1558-8238

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 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in cultured human dermal fibroblasts (HDFs). Here, we determined 11β-HSD1 levels in human skin biopsies from young and older volunteers and examined the aged 11β-HSD1 KO mouse skin phenotype. 11β-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 11β-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 11β-HSD1 inhibitor treatment accelerated healing of full-thickness mouse dorsal wounds, with improved healing also observed in aged 11β-HSD1 KO mice. These findings suggest that elevated 11β-HSD1 activity in aging skin leads to increased local GC generation, which may account for adverse changes occurring in the elderly, and 11β-HSD1 inhibitors maybe useful in the treatment of age-associated impairments in dermal integrity and wound healing. [PUBLICATION ABSTRACT]