(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 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 1 alpha, 25- dihydroxyvitamin D-3 [ 1 alpha, 25-( OH) D-2(3)] and can form OCLs at physiologic concentrations of 1 alpha, 25( OH) D-2(3). This hyperresponsivity to 1 alpha, 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 1 alpha, 25-( OH)(2)D-3 may permit OCL formation in PD patients with low levels of 1 alpha, 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- 1 alpha- 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 1 alpha, 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 1 alpha,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 1 alpha, 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 1 alpha, 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.