Regulation of keratinocyte growth, differentiation, and vitamin D metabolism by analogs of 1,25-dihydroxyvitamin D

Abstract

1,25(OH)2D has numerous actions on many tissues. Analogs of 1,25(OH)2D are being sought that are selective, to further an understanding of the mechanisms of action of 1,25(OH)2D and to improve its therapeutic efficacy. Toward these ends we examined eight analogs of 1,25(OH)2D for their ability to regulate 25OHD metabolism by keratinocytes. Choosing the three most potent, we then examined their ability to inhibit keratinocyte proliferation, stimulate cornified envelope formation (a marker of differentiation), and bind to the 1,25(OH)2D receptor (VDR). 1,25(OH)2-24F2-D, 1,25(OH)2-Δ16-D, and 1,25(OH)2-Δ16,23yne-D proved the most potent in inhibiting 1,25(OH)2D production and stimulating 24,25(OH)2D production, being approximately 10-100 times more potent than 1,25(OH)2D itself. 1,25(OH)2-Δ16-D had the highest affinity for the VDR (fourfold higher than that for 1,25(OH)2D itself) and had the greatest ability both to inhibit proliferation and to stimulate differentiation. 1,25(OH)2-Δ16,23yne-D also had a higher affinity for the VDR but was of less or equal potency in stimulating cornified envelope formation and inhibiting proliferation. 1,25(OH)2-24F2-D, which was the most potent regulator of 250HD metabolism, had a lower affinity for the VDR and was less potent than 1,25(OH)2D in inhibiting proliferation. Our results indicate that even in the same cell different analogs have different rank orders of potency for the various actions of 1,25(OH)2D. © 1993.