TY - JOUR
T1 - The effects of MC903 on 1,25-(OH)2D3 receptor binding, 24-hydroxylase activity and in vitro bone resorption
AU - Pols, H. A.P.
AU - Birkenhäger, J. C.
AU - Schilte, J. P.
AU - Bos, M. P.
AU - van Leeuwen, J. P.T.M.
PY - 1991/8
Y1 - 1991/8
N2 - MC903, a new vitamin D analog has been shown to exert potent effects on cell proliferation and differentiation, while in vivo a decreased activity on calcium metabolism has been observed. In the osteoblast-like cell line UMR-106, MC903 displaces tritiated 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) from its receptor at least as efficiently as 1,25-(OH)2D3. The effect of MC903 on 1,25-(OH)2D3 receptor up-regulation in UMR-106 cells and on bone resorption in fetal mouse radii/ulnae was comparable to that of 1,25-(OH)2D3. MC903 was about 50% less effective in inducing 24-hydroxylase activity and the subsequent C24-side chain oxidation of 25-(OH)D3 compared to 1,25-(OH)2D3. Ketoconazole did not potentiate MC903-induced 1,25-(OH)2D3 receptor up-regulation as was found with 1,25-(OH)2D3 which suggests that the C24-oxidation plays a minor role in the inactivation of MC903. Nevertheless, the comparable effects of MC903 and 1,25-(OH)2D3 on in vitro bone resorption indicate that the lower effectivity of MC903 on bone calcium mobilization in vivo has to be due to a higher metabolic clearance rate.
AB - MC903, a new vitamin D analog has been shown to exert potent effects on cell proliferation and differentiation, while in vivo a decreased activity on calcium metabolism has been observed. In the osteoblast-like cell line UMR-106, MC903 displaces tritiated 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) from its receptor at least as efficiently as 1,25-(OH)2D3. The effect of MC903 on 1,25-(OH)2D3 receptor up-regulation in UMR-106 cells and on bone resorption in fetal mouse radii/ulnae was comparable to that of 1,25-(OH)2D3. MC903 was about 50% less effective in inducing 24-hydroxylase activity and the subsequent C24-side chain oxidation of 25-(OH)D3 compared to 1,25-(OH)2D3. Ketoconazole did not potentiate MC903-induced 1,25-(OH)2D3 receptor up-regulation as was found with 1,25-(OH)2D3 which suggests that the C24-oxidation plays a minor role in the inactivation of MC903. Nevertheless, the comparable effects of MC903 and 1,25-(OH)2D3 on in vitro bone resorption indicate that the lower effectivity of MC903 on bone calcium mobilization in vivo has to be due to a higher metabolic clearance rate.
UR - http://www.scopus.com/inward/record.url?scp=0025783239&partnerID=8YFLogxK
U2 - 10.1016/0169-6009(91)90087-G
DO - 10.1016/0169-6009(91)90087-G
M3 - Article
C2 - 1655130
AN - SCOPUS:0025783239
SN - 0169-6009
VL - 14
SP - 103
EP - 111
JO - Bone and Mineral
JF - Bone and Mineral
IS - 2
ER -