Increased glucocorticoid activation during mouse skin wound healing

• Published in: Journal of endocrinology Vol. 221; no. 1; pp. 51 - 61
• Main Authors: Tiganescu, Ana, Hupe, Melanie, Uchida, Yoshikazu, Mauro, Theodora, Elias, Peter M, Holleran, Walter M
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01-04-2014
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; 11-beta-Hydroxysteroid Dehydrogenase Type 2 - genetics; 11-beta-Hydroxysteroid Dehydrogenase Type 2 - metabolism; Animals; Female; Glucocorticoids - metabolism; Humans; Mice; Mice, Hairless; Receptors, Glucocorticoid - metabolism; Skin - enzymology; Skin Physiological Phenomena; Wound Healing; 11β-hydroxysteroid dehydrogenase; steroidogenesis; skin; glucocorticoid; wound healing
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1530/JOE-13-0420

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.