Inhibition of glucocorticoid-induced epidermal and dermal atrophy with KH 1060--a potent 20-epi analogue of 1,25-dihydroxyvitamin D3.
1. The possibility of preventing and treating glucocorticoid-induced skin atrophy with KH 1060 (the potent 20-epi-22-oxa-24a-homo-26,27-dimethyl analogue of 1,25-dihydroxyvitamin D3) was examined in a hairless mouse model. 2. KH 1060 (0.625-6.25 pmol cm-2 of skin) applied topically for 7 days together with 2.5 nmol cm-2 betamethasone-17-valerate prevented, in a concentration-dependent manner, the development of epidermal, dermal and total skin thinning caused by the glucocorticoid. The effect of KH 1060 on the epidermis occurred at a lower dose than on the dermis, and at doses above 1.25 pmol cm-2 KH 1060 caused epidermal hyperplasia. 3. KH 1060 (2.5 pmol cm-2) prevented the development of betamethasone-associated skin atrophy in mice during a long-term (4 weeks) treatment, and reversed established cutaneous glucocorticoid atrophy. 4. Radiolabelling experiments with [35S]-sulphate and [3H]-proline in vivo revealed that KH 1060 stimulated the synthesis of sulphated glycosaminoglycans and hydroxyproline in skin treated with betamethasone. 5. These findings strongly suggest that KH 1060 prevents and reverses glucocorticoid-induced skin atrophy by stimulating epidermal proliferation and enhancing synthesis of extracellular matrix in the dermis.
Department of Dermatological Research, Leo Pharmaceutical Products, Ballerup, Denmark.
R
R
Gniadecki
M
M
Gniadecka
J
J
Serup
D000818:Animals; D001284:Atrophy / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D001624:Betamethasone Valerate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D004817:Epidermis / Q000473:pathology; D005260:Female; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D006025:Glycosaminoglycans / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008812:Mice, Hairless; D008809:Mice, Inbred C3H; D012867:Skin / Q000473:pathology*; D012885:Skinfold Thickness; D013462:Sulfur Radioisotopes
D005938:Glucocorticoids; D006025:Glycosaminoglycans; D007166:Immunosuppressive Agents; D013462:Sulfur Radioisotopes; C074279:KH 1060; D001624:Betamethasone Valerate; D002117:Calcitriol; D006909:Hydroxyproline; D002118:Calcium