title: Nonhypercalcemic 1,25-(OH)2D3 analogs potently induce the human osteocalcin gene promoter stably transfected into rat osteosarcoma cells (ROSCO-2).
abstract: 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] is the active hormonal form of vitamin D3 and has potent effects on bone and calcium regulation. Over the past decade it has become apparent that 1,25-(OH)2D3 has other effects on cellular proliferation that potentially could be developed for therapy in human malignancy. Since the hypercalcemic effects of 1,25-(OH)2D3 have limited that use in the human, novel nonhypercalcemic analogs of 1,25-(OH)2D3 have been synthesized. The molecular mechanism of this divergence in these antiproliferative and calcium-regulating actions is unexplained. We have previously examined the human bone-specific gene osteocalcin as a model of the molecular mechanisms of vitamin D action in bone and have shown that induction of the osteocalcin gene by 1,25-(OH)2D3 is mediated through an unique and complex palindromic region of the promoter similar to but distinct from those of other steroid hormone-responsive elements. Using an osteosarcoma cell line permanently transfected with the vitamin D-responsive promoter of the human osteocalcin gene linked to a "reporter" gene, we have shown that there is a dose-dependent induction of CAT activity by 1,25-(OH)2D3 and that the potencies of vitamin D metabolites and analogs are comparable to those found in other vitamin D bioassays. Furthermore, vitamin D analogs, including MC-903, 22-oxa-1,25-(OH)2D3, and delta 22-1,25S,26-trihydroxyvitamin D3, which effect cellular differentiation but lack hypercalcemic activity in vivo, exhibit osteocalcin promoter inductive actions virtually identical to those of 1,25-(OH)2D3. Consideration of these and other data support the hypothesis that the divergent effects of such analogs on differentiation and calcium homeostasis reflect pharmacokinetic differences in vivo rather than distinct 1,25-(OH)2D3-sensitive pathways.
authors.affiliation: Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia.
authors.forename: N A
authors.initials: NA
authors.lastname: Morrison
authors.forename: J A
authors.initials: JA
authors.lastname: Eisman
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D006887:Hydroxycholecalciferols / Q000494:pharmacology; D015675:Osteocalcin / Q000235:genetics*; D012516:Osteosarcoma; D011401:Promoter Regions, Genetic; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D006887:Hydroxycholecalciferols; D015675:Osteocalcin; C055085:calcipotriene; C072826:delta-22-1,25S,26-trihydroxyvitamin D3; D002117:Calcitriol; C051883:maxacalcitol; D002118:Calcium