INHIBITION OF PROLIFERATION AND INDUCTION OF DIFFERENTIATION OF OSTEOBLASTIC CELLS BY A NOVEL 1,25-DIHYDROXYVITAMIN D-3 ANALOG WITH AN EXTENSIVELY MODIFIED SIDE-CHAIN (CB1093)

Citation
S. Ryhanen et al., INHIBITION OF PROLIFERATION AND INDUCTION OF DIFFERENTIATION OF OSTEOBLASTIC CELLS BY A NOVEL 1,25-DIHYDROXYVITAMIN D-3 ANALOG WITH AN EXTENSIVELY MODIFIED SIDE-CHAIN (CB1093), Journal of cellular biochemistry, 70(3), 1998, pp. 414-424
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biology,"Cell Biology
ISSN journal
0730-2312
Volume
70
Issue
3
Year of publication
1998
Pages
414 - 424
Database
ISI
SICI code
0730-2312(1998)70:3<414:IOPAIO>2.0.ZU;2-T
Abstract
1,25-Dihydroxyvitamin D-3 (1,25 D) is involved in the regulation of pr oliferation and differentiation of a variety of cell types including c ancer cells. In recent years, numerous new vitamin D-3 analogs have be en developed in order to obtain favorable therapeutic properties. The effects of a new 20-epi analog, CB1093 xy-23-yne-24a,26a,27a-trihomo-a lpha,25(OH)(2)D-3), on the proliferation and differentiation of human MG-63 osteosarcoma cell line were compared here with those of the pare nt compound 1,25D. Proliferation of the MC-63 cells was inhibited simi larly by 22%, 50% and 59% after treatment with 0.1 mu M 7,25D or CB109 3 fur 48 h, 96 h, and 144 h, respectively. In transfection experiments , the compounds were equipotent in stimulating reporter gene activity under the control of human osteocalcin gene promoter. In cell culture experiments, however, CB1093 was more potent than 1,25D at low concent rations and more effective for a longer period of time in activating t he osteocalcin gene expression at mRNA and protein levels. Also, a 6-h pretreatment and subsequent culture for up to 120 h without 1,25D or CB1093 yielded higher osteocalcin mRNA and protein levels with analog- treated cells than with 1,25D-treated cells. The electrophoretic mobil ity shift assay (EMSA) revealed stronger VDR-VDRE binding with analog- treated MG-63 cells than with 1,25D-treated cells. The differences in the DNA binding of 1,25D-bound vs, analog bound VDR, however, largely disappeared when the binding reactions were performed with recombinant hVDR and hRXR beta proteins. These results demonstrate that the new a nalog CB1093 was equally or even more effective than 1,25D in regulati ng all human osteosarcoma cell functions ranging from growth inhibitio n to marker gene expression and that the differences in effectivity mo st probably resulted from interactions of the hVDR:hRXR beta-complex w ith additional nuclear proteins. J. Cell. Biochem. 70:414-424, 1998. ( C) 1998 Wiley-Liss. Inc.