The effects of MC903 on 1,25-(OH)₂D₃ receptor binding, 24-hydroxylase activity and in vitro bone resorption

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.