ABSTRACT
A new highly potent analogue (KH-1060) of vitamin D3 has been recently shown to stimulate the growth and differentiation of keratinocytes. This study was intended to determine the effects of this new analogue on epidermis at the ultrastructural level. KH-1060 was applied topically on the backs of hairless mice for 4 weeks; the skin was then studied by routine electron microscopy. The effects were compared with those of betamethasone-17-valerate and with concomitant treatment of KH-1060 following betamethasone. KH-1060 stimulated normal function of keratinocytes and formed a thick epidermis. The ultrastructure of the thick epidermis represents an enhanced normal process of keratinization and proliferation. Moreover, KH-1060 diminished the atrophogenic effects of betamethasone.
Subject(s)
Calcitriol/analogs & derivatives , Epidermis/drug effects , Epidermis/ultrastructure , Administration, Cutaneous , Animals , Atrophy , Betamethasone Valerate/administration & dosage , Betamethasone Valerate/antagonists & inhibitors , Betamethasone Valerate/pharmacology , Calcitriol/administration & dosage , Calcitriol/pharmacology , Cell Differentiation/drug effects , Cell Division/drug effects , Cytoplasm/drug effects , Cytoplasm/ultrastructure , Cytoplasmic Granules/drug effects , Cytoplasmic Granules/ultrastructure , Desmosomes/drug effects , Desmosomes/ultrastructure , Female , Hyalin/drug effects , Hyalin/metabolism , Intermediate Filaments/drug effects , Intermediate Filaments/ultrastructure , Keratinocytes/drug effects , Keratinocytes/ultrastructure , Keratins/drug effects , Keratins/metabolism , Mice , Mice, Hairless , Microscopy, Electron , Mitochondria/drug effects , Mitochondria/ultrastructure , Ribosomes/drug effects , Ribosomes/ultrastructureABSTRACT
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.
