Vitamin D antagonist, TEI-9647, inhibits osteoclast formation induced by 1alpha,25-dihydroxyvitamin D3 from pagetic bone marrow cells.
(23S)-25-Dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647) functions an antagonist of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) 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 1alpha,25-(OH)(2)D(3) 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 1alpha,25-(OH)(2)D(3) (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 1alpha,25-(OH)(2)D(3) dependent gene expression, but almost completely suppressed TAF(II)-17, a potential coactivator of VDR and 25-hydroxyvitamin D(3)-24-hydroxylase (25-OH-D(3)-24-hydroxylase) gene expression induced by 10(-10)M 1alpha,25-(OH)(2)D(3) in bone marrow cells of patients with Paget's disease. Moreover, TEI-9647 dose-dependently inhibited bone resorption induced by 10(-9)M 1alpha,25-(OH)(2)D(3) 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.
Ishizuka
Seiichi
S
Department of Bone and Calcium Metabolism, Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan. s.ishizuka@teijin.co.jp
Kurihara
Noriyoshi
N
Miura
Daishiro
D
Takenouchi
Kazuya
K
Cornish
Jillian
J
Cundy
Tim
T
Reddy
Sakamuri V
SV
Roodman
G David
GD
D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D001862:Bone Resorption; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D010001:Osteitis Deformans / Q000473:pathology*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D014807:Vitamin D / Q000037:antagonists & inhibitors* / Q000097:blood
D017931:DNA Primers; C400545:TEI 9647; D014807:Vitamin D; D002117:Calcitriol