11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects
Ana Tiganescu, … , Gareth G. Lavery, Paul M. Stewart
Ana Tiganescu, … , Gareth G. Lavery, Paul M. Stewart
Published June 3, 2013
Citation Information: J Clin Invest. 2013;123(7):3051-3060. https://doi.org/10.1172/JCI64162.
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Research Article Aging

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

Abstract

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 may be useful in the treatment of age-associated impairments in dermal integrity and wound healing.

Authors

Ana Tiganescu, Abd A. Tahrani, Stuart A. Morgan, Marcela Otranto, Alexis Desmoulière, Lianne Abrahams, Zaki Hassan-Smith, Elizabeth A. Walker, Elizabeth H. Rabbitt, Mark S. Cooper, Kurt Amrein, Gareth G. Lavery, Paul M. Stewart

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Figure 5

Improved collagen synthesis gene expression in aged 11β-HSD1–null mice.

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Improved collagen synthesis gene expression in aged 11β-HSD1–null mice. ...
(A) Expression of the prolyl hydroxylase LEPREL1 decreased in the aged WT mice (n = 3) relative to the younger animals (n = 5). This was reversed in the aged KO mice (n = 4). (B) Similarly, the age-induced decrease in lysyl hydroxylase PLOD1 expression was partially rescued in aged KO mice. (C) TIMP4 expression was also reduced in aged WT, but not KO, mice relative to young WT mice. (D) COL1A1 expression was unaltered with age or genotype. (E and F) An age-induced decrease in MMP2 and MMP3 was also observed but was unaffected by genotype. *P < 0.05; **P < 0.01; ***P < 0.001. NS, nonsignificant.