SYNTHETIC 20-EPI ANALOGS OF CALCITRIOL ARE POTENT INDUCERS OF TARGET-GENE ACTIVATION IN OSTEOBLASTIC CELLS

Citation
S. Ryhanen et al., SYNTHETIC 20-EPI ANALOGS OF CALCITRIOL ARE POTENT INDUCERS OF TARGET-GENE ACTIVATION IN OSTEOBLASTIC CELLS, European journal of biochemistry, 238(1), 1996, pp. 97-103
Citations number
28
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biology
ISSN journal
0014-2956
Volume
238
Issue
1
Year of publication
1996
Pages
97 - 103
Database
ISI
SICI code
0014-2956(1996)238:1<97:S2AOCA>2.0.ZU;2-P
Abstract
We have compared the actions of calcitriol and its three synthetic ana logs; 20-epi-22-oxa-24a,26a,27a-trihomo-1 alpha,25-dihydroxyvitamin D- 3 (KH 1060), 1 alpha,24S-(OH)(2)-22-ene-26,27-cyclopropyl vitamin D-3 (MC 903) and 20-epi-1 alpha,25-dihydroxyvitamin D-3 (MC 1288), on the expression of two marker genes of differentiated osteoblasts, namely a lkaline phosphatase and osteocalcin, using human MG-63 osteosarcoma ce lls. Calcitriol and the analogs had qualitatively similar stimulatory effects on target-gene activation. Quantitatively, MC 903 behaved in m ost experiments essentially as the parent compound calcitriol. In vita min D receptor/DNA complex formation MC 903, however, was more potent than calcitriol. In contrast, the 20-epi analogs, KH 1060 and MC 1288, were much more potent even at lower concentrations, than calcitriol a nd MC 903 in stimulating alkaline phosphatase activity, osteocalcin mR NA synthesis and osteocalcin secretion. The stimulation occurred to a greater degree and for a longer period than with calcitriol. This effe ct was apparently mediated by stronger and longer lasting binding of t he vitamin D receptor to the osteocalcin vitamin D responsive element by the 20-epi analogs. After a 6-h treatment and during subsequent cul ture without hormone, the effects of the 20-epi analogs were also stro nger and lasted longer than those with calcitriol or MC 903. Collectiv ely, at comparable and lower concentrations, the 20-epi analogs, KH 10 60 and MC 1288, mediate much stronger and longer lasting stimulatory e ffects than calcitriol or its analog MC 903 on target-gene expression associated with the differentiated phenotype of the MG-63 human osteos arcoma cells.