Calcitriol and its analog KH 1060 induce similar changes in keratinocyte cell cycle progression after topical application to mouse skin. A bromodeoxyuridine pulse-chase flow cytometric study.
Calcitriol and its analogs are used in the treatment of psoriasis and may also induce epidermal proliferation, hyperplasia, and irritation in normal skin by an unknown mechanism. The effects of a single dose of calcitriol and the 20-epi-vitamin D3 analog KH 1060 were therefore examined by performing 5-bromo-2'-deoxyuridine (BrdU) pulse chase labeling experiments in unperturbed hairless mouse epidermis in vivo. One cohort of basal cells was exposed to calcitriol mainly during the S phase, whereas another cohort in G1/G0 phase was stimulated by calcitriol or KH 1060 into S phase 16 h before BrdU labeling. Basal keratinocytes were isolated from epidermis and analyzed by bivariate BrdU/DNA flow cytometry. Calcitriol and KH 1060 induced similar proliferative responses, with a peak of cells in S phase at about 16 h after drug applications. The cohorts in G1/G0 phase at the time of drug application displayed a reduced cell cycle, whereas the cohort of cells in S phase at the time of calcitriol application did not show a similar reduction. The proliferation kinetics observed are thus different from those seen after retinoic acid treatment, since retinoic acid did not reduce the cell cycle time under similar conditions. Reduction of cell cycle time may be a characteristic effect of calcitriol and KH 1060, similar to that seen after other hyperplasiogens. The results also indicate that the drugs exert differential effects on cells depending on the cells' position in the cell cycle during treatment.
Lützow-Holm
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Institute of Pathology, University of Oslo, National Hospital, Rikshospitalet, Norway.
De Angelis
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Clausen
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D000287:Administration, Topical; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism*; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D005434:Flow Cytometry; D015603:Keratinocytes / Q000187:drug effects*; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008809:Mice, Inbred C3H; D016196:S Phase / Q000187:drug effects
C074279:KH 1060; D002117:Calcitriol; D001973:Bromodeoxyuridine