(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.
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.
Ishizuka
Seiichi
S
Veterans Affairs Pittsburgh Healthcare System, Research and Development (151-U), University Drive, Pittsburgh, Pennsylvania 15240, USA.
Kurihara
Noriyoshi
N
Reddy
Sakamuri V
SV
Cornish
Jillian
J
Cundy
Tim
T
Roodman
G David
GD
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
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