(23S)-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone, a vitamin D receptor antagonist that inhibits osteoclast formation and bone resorption in bone marrow cultures front patients with Paget's disease

Seiichi Ishizuka, Noriyoshi Kurihara, Sakamuri V. Reddy, Julian Cornish, Tim Gundy, G. David Roodman

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Abstract

Osteoclast (OCL) precursors from patients with Paget's disease (PD) and normal OCL precursors transduced with the measles virus nucleocapsid protein gene (MVNP) are hyperresponsive to 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2D3] and can form OCLs at physiologic concentrations of 1α,25-(OH)2D3. This hyperresponsivity to 1α,25-(OH)2D3 is due to increased expression of TATA box-associated factor II-17, a potential coactivator of the vitamin D receptor. Hyperresponsivity to 1α,25-(OH) 2D3 may permit OCL formation in PD patients with low levels of 1α,25-(OH)2D3 and play a role in the pathogenesis of PD. Therefore, we tested the effects of a vitamin D antagonist, (23S)-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone (TEI-9647), to determine its potential to inhibit the enhanced OCL formation and bone resorption seen in patients with PD. TEI-9647, by itself, was not a vitamin D receptor agonist and did not induce OCL formation in vitro, even at 10 -6 M. However, it dose-dependently (10-10 M to 10 -6 M) inhibited osteoclast formation induced by concentrations of 1α,25-(OH)2D3 (41 pg/ml, 10-10 M) detected in PD patients by bone marrow cells of patients with PD and MVNP-transduced colony-forming unit-granulocyte macrophage (CFU-GM) cells, which form pagetic-like OCL. Moreover, bone resorption by OCLs derived from MVNP-transduced CFU-GM treated with 10-9 M 1α,25-(OH) 2D3 was dose-dependently inhibited by TEI-9647 (10 -9 M to 10-6 M). Furthermore, 10-7 M TEI-9647 by itself did not cause 1α,25-(OH)2D3-dependent gene expression but almost completely suppressed expression of the TATA box-associated factor II-17 and 25-hydroxyvitamin D3-24-hydroxylase genes induced by 1α,25-(OH)2D3 treatment of MVNP-transduced CFU-GM cells. These results demonstrate that TEI-9647 can suppress the excessive bone resorption and OCL formation seen in marrow cultures from patients with PD.

Original languageEnglish (US)
Pages (from-to)2023-2030
Number of pages8
JournalEndocrinology
Volume146
Issue number4
DOIs
StatePublished - Apr 1 2005

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ASJC Scopus subject areas

  • Endocrinology

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