THE EFFECTS OF KH-1060, A POTENT 20-EPI ANALOG OF THE VITAMIN-D-3 HORMONE, ON HAIRLESS MOUSE SKIN IN-VIVO

Dermal effects of KH 1060, a novel, highly potent 20-epi analogue of 1 alpha,25-dihyroxyvitamin D-3, were investigated in a hairless mouse m odel, During daily topical applications of a 0.4 mu M solution of KH 1 060 for 4 weeks, epidermal hyperplasia and an increase of dermal thick ness and mass were observed. KH 1060 upregulated glycosaminoglycan and collagen synthesis in the skin, and increased glycosaminoglycan depos ition in the subepidermal region, Reverse transcription-polymerase cha in reaction amplification of the transforming growth factor (TGF) beta 1-specific mRNA revealed that KH 1060 stimulated expression of this g rowth factor in the epidermis, but not in the dermis, Changes observed after application of 1 alpha,25-dihydroxyvitamin D-3 were much less p ronounced but qualitatively similar to the effects of KH 1060, whereas structurally related but receptor inactive compounds, vitamin D-3 and 1 beta,25-dihydroxyvitamin D-3, did not produce any effects. Furtherm ore, we were unable to demonstrate the involvement of the non-genomic, receptor-independent vitamin D signalling in the skin, using a specif ic stimulator (Ro 24-2090) and a blocker (1 beta,25-dihydroxyvitamin D -3) Of this pathway. Our findings provide the first evidence that a st rong Vitamin D-3 analogue triggers synthesis of skin connective tissue , possibly via vitamin D receptor activation and the paracrine action of epidermis-derived TGF-beta 1.