title: (23S)-25-Dehydro-1{alpha}-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.
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 1alpha,25-dihydroxyvitamin D(3) [1alpha,25-(OH)(2)D(3)] and can form OCLs at physiologic concentrations of 1alpha,25-(OH)(2)D(3). This hyperresponsivity to 1alpha,25-(OH)(2)D(3) is due to increased expression of TATA box-associated factor II-17, a potential coactivator of the vitamin D receptor. Hyperresponsivity to 1alpha,25-(OH)(2)D(3) may permit OCL formation in PD patients with low levels of 1alpha,25-(OH)(2)D(3) and play a role in the pathogenesis of PD. Therefore, we tested the effects of a vitamin D antagonist, (23S)-25-dehydro-1alpha-hydroxyvitamin D(3)-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 1alpha,25-(OH)(2)D(3) (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 1alpha,25-(OH)(2)D(3) 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 1alpha,25-(OH)(2)D(3)-dependent gene expression but almost completely suppressed expression of the TATA box-associated factor II-17 and 25-hydroxyvitamin D(3)-24-hydroxylase genes induced by 1alpha,25-(OH)(2)D(3) 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.
authors.affiliation: Veterans Affairs Pittsburgh Healthcare System, Research and Development (151-U), University Drive, Pittsburgh, Pennsylvania 15240, USA.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Ishizuka
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Kurihara
authors.forename: Sakamuri V
authors.initials: SV
authors.lastname: Reddy
authors.forename: Jillian
authors.initials: J
authors.lastname: Cornish
authors.forename: Tim
authors.initials: T
authors.lastname: Cundy
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
mesh_terms: D001854:Bone Marrow Cells / Q000187:drug effects; D001862:Bone Resorption / Q000517:prevention & control*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D006801:Humans; D010001:Osteitis Deformans / Q000188:drug therapy*; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors* / Q000502:physiology; D013250:Steroid Hydroxylases / Q000235:genetics; D035362:Transcription Factor TFIID / Q000235:genetics / Q000502:physiology; D014807:Vitamin D / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D018167:Receptors, Calcitriol; C400545:TEI 9647; D035362:Transcription Factor TFIID; D014807:Vitamin D; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol