Increased glucocorticoid activation during mouse skin wound healing.
Glucocorticoid (GC) excess inhibits wound healing causing increased patient discomfort and infection risk. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates GCs (converting 11-dehydrocorticosterone to corticosterone in rodents) in many tissues including skin, where de novo steroidogenesis from cholesterol has also been reported. To examine the regulation of 11β-HSD1 and steroidogenic enzyme expression during wound healing, 5 mm wounds were generated in female SKH1 mice and compared at days 0, 2, 4, 8, 14, and 21 relative to unwounded skin. 11β-HSD1 expression (mRNA and protein) and enzyme activity were elevated at 2 and 4 days post-wounding, with 11β-HSD1 localizing to infiltrating inflammatory cells. 11β-HSD2 (GC-deactivating) mRNA expression and activity were undetectable. Although several steroidogenic enzymes displayed variable expression during healing, expression of the final enzyme required for the conversion of 11-deoxycorticosterone to corticosterone, 11β-hydroxylase (CYP11B1), was lacking in unwounded skin and post-wounding. Consequently, 11-deoxycorticosterone was the principal progesterone metabolite in mouse skin before and after wounding. Our findings demonstrate that 11β-HSD1 activates considerably more corticosterone than is generated de novo from progesterone in mouse skin and drives GC exposure during healing, demonstrating the basis for 11β-HSD1 inhibitors to accelerate wound repair.
Department of Dermatology, University of California San Francisco, 1700 Owens Street, San Francisco, California 94158, USA.
Ana
A
Tiganescu
Melanie
M
Hupe
Yoshikazu
Y
Uchida
Theodora
T
Mauro
Peter M
PM
Elias
Walter M
WM
Holleran
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012867:Skin / Q000201:enzymology; D012879:Skin Physiological Phenomena; D014945:Wound Healing
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2
11β-hydroxysteroid dehydrogenase; glucocorticoid; skin; steroidogenesis; wound healing