Vitamin D antagonist, TEI-9647, inhibits osteoclast formation induced by 1α,25-dihydroxyvitamin D3 from pagetic bone marrow cells

Seiichi Ishizuka, Noriyoshi Kurihara, Daishiro Miura, Kazuya Takenouchi, Jillian Cornish, Tim Cundy, Sakamuri V. Reddy, G. David Roodman

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

(23S)-25-Dehydro-1α-hydroxyvitamin D3-26,23-lactone (TEI-9647) functions an antagonist of the 1α,25-dihydroxyvitamin D 3 (1α,25-(OH)2D3) 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 1α,25-(OH)2D3 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 1α,25-(OH)2D3 (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 1α,25-(OH)2D3 dependent gene expression, but almost completely suppressed TAFII-17, a potential coactivator of VDR and 25-hydroxyvitamin D3-24-hydroxylase (25-OH-D3-24- hydroxylase) gene expression induced by 10-10 M 1α,25-(OH) 2D3 in bone marrow cells of patients with Paget's disease. Moreover, TEI-9647 dose-dependently inhibited bone resorption induced by 10-9 M 1α,25-(OH)2D3 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.

Original languageEnglish (US)
Pages (from-to)331-334
Number of pages4
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume89-90
DOIs
StatePublished - May 1 2004

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Keywords

  • Bone resorption
  • Coactivator
  • Measles virus
  • Osteoclast
  • Paget's disease
  • Vitamin D antagonist
  • Vitamin D receptor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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