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(23S)-25-Dehydro-1-Hydroxyvitamin D₃-26,23-Lactone, a Vitamin D Receptor Antagonist that Inhibits Osteoclast Formation and Bone Resorption in Bone Marrow Cultures from Patients with Paget’s Disease

Teijin Institute for Bio-Medical Research (S.I.), Tokyo 191-8512, Japan; Division of Hematology/Oncology (S.I., N.K., S.V.R., G.D.R.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Medicine (J.C., T.C.), University of Auckland, Auckland 92019, New Zealand; and Veterans Affairs Pittsburgh Healthcare System (G.D.R.), Pittsburgh, Pennsylvania 15240

Address all correspondence and requests for reprints to: G. David Roodman, M.D., Ph.D., Veterans Affairs Pittsburgh Healthcare System, Research and Development (151-U), University Drive, Pittsburgh, Pennsylvania 15240. E-mail: roodmangd{at}upmc.edu.

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 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] and can form OCLs at physiologic concentrations of 1,25-(OH)₂D₃. This hyperresponsivity to 1,25-(OH)₂D₃ is due to increased expression of TATA box-associated factor II-17, a potential coactivator of the vitamin D receptor. Hyperresponsivity to 1,25-(OH)₂D₃ may permit OCL formation in PD patients with low levels of 1,25-(OH)₂D₃ and play a role in the pathogenesis of PD. Therefore, we tested the effects of a vitamin D antagonist, (23S)-25-dehydro-1-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 1,25-(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 1,25-(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 1,25-(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 1,25-(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.

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