Document Detail

Vitamin D antagonist, TEI-9647, inhibits osteoclast formation induced by 1alpha,25-dihydroxyvitamin D3 from pagetic bone marrow cells.
MedLine Citation:
PMID:  15225795     Owner:  NLM     Status:  MEDLINE    
(23S)-25-Dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647) functions an antagonist of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells [J. Biol. Chem. 274 (1999) 16392]. We examined the effect of vitamin D antagonist, TEI-9647, on osteoclast formation induced by 1alpha,25-(OH)(2)D(3) from bone marrow cells of patients with Paget's disease. TEI-9647 itself never induced osteoclast formation even at 10(-6)M, but dose-dependently (10(-10) to 10(-6)M) inhibited osteoclast formation induced by physiologic concentrations of 1alpha,25-(OH)(2)D(3) (41 pg/ml, 10(-10)M) from bone marrow cells of patients with Paget's disease. At the same time, 10(-8)M of TEI-9647 alone did not cause 1alpha,25-(OH)(2)D(3) dependent gene expression, but almost completely suppressed TAF(II)-17, a potential coactivator of VDR and 25-hydroxyvitamin D(3)-24-hydroxylase (25-OH-D(3)-24-hydroxylase) gene expression induced by 10(-10)M 1alpha,25-(OH)(2)D(3) in bone marrow cells of patients with Paget's disease. Moreover, TEI-9647 dose-dependently inhibited bone resorption induced by 10(-9)M 1alpha,25-(OH)(2)D(3) by osteoclasts produced by RANKL and M-CSF treatment of measles virus nucleocapsid gene transduced bone marrow cells. These results suggest that TEI-9647 acts directly on osteoclast precursors and osteoclasts, and that TEI-9647 may be a novel agent to suppress the excessive bone resorption and osteoclast formation in patients with Paget's disease.
Seiichi Ishizuka; Noriyoshi Kurihara; Daishiro Miura; Kazuya Takenouchi; Jillian Cornish; Tim Cundy; Sakamuri V Reddy; G David Roodman
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of steroid biochemistry and molecular biology     Volume:  89-90     ISSN:  0960-0760     ISO Abbreviation:  J. Steroid Biochem. Mol. Biol.     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-06-30     Completed Date:  2004-08-31     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  9015483     Medline TA:  J Steroid Biochem Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  331-4     Citation Subset:  IM    
Department of Bone and Calcium Metabolism, Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan.
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MeSH Terms
Base Sequence
Bone Marrow Cells / cytology,  drug effects*
Bone Resorption
Calcitriol / analogs & derivatives*,  pharmacology*
DNA Primers
Gene Expression Regulation / drug effects
Osteitis Deformans / pathology*
Osteoclasts / cytology,  drug effects*
Vitamin D / antagonists & inhibitors*,  blood
Reg. No./Substance:
0/DNA Primers; 0/TEI 9647; 1406-16-2/Vitamin D; 32222-06-3/Calcitriol

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