The Vitamin D Receptor In Osteoblast-Lineage Cells Is Essential For The Proresorptive Activity Of 1 Alpha,25(Oh)(2)D-3 In Vivo

We previously reported that daily administration of a pharmacological dose of eldecalcitol, an analog of 1 alpha,25-dihydroxyvitamin D-3[1 alpha,25(OH)(2)D-3], increased bone mass by suppressing bone resorption.These antiresorptive effects were found to be mediated by the vitamin D receptor (VDR) in osteoblast-lineage cells. Using osteoblast-lineage-specific VDR conditional knockout (Ob-VDR-cKO) mice, we examined whether proresorptive activity induced by the high-dose 1 alpha,25(OH)(2)D-3 was also mediated by VDR in osteoblastlineage cells. Administration of 1 alpha,25(OH)(2)D-3 (5 mu g/kg body weight/day) to wild-type mice for 4 days increased the number of osteoclasts in bone and serum concentrations of C-terminal crosslinked telopeptide of type I collagen (CTX-I, a bone resorption marker). The stimulation of bone resorption was concomitant with the increase in serum calcium (Ca) and fibroblast growth factor 23 (FGF23) levels, and decrease in body weight.This suggests that a toxic dose of 1 alpha,25(OH)(2)D-3 can induce bone resorption and hypercalcemia. In contrast, pretreatment of wild-type mice with neutralizing anti-receptor activator of NF-kappa B ligand (RANKL) antibody inhibited the 1 alpha,25(OH)(2)D-3-induced increase of osteoclast numbers in bone, and increase of CTX-I, Ca, and FGF23 levels in serum. The pretreatment with anti-RANKL antibody also inhibited the 1 alpha,25(OH)(2)D-3-induced decrease in body weight. Consistent with observations in mice conditioned with anti-RANKL antibody, the high-dose administration of 1 alpha,25(OH)(2)D-3 to Ob-VDR-cKO mice failed to significantly increase bone osteoclast numbers, serum CTX-I, Ca, or FGF23 levels, and failed to reduce the body weight.Taken together, this study demonstrated that the proresorptive, hypercalcemic, and toxic actions of high-dose 1 alpha,25(OH)(2)D-3 are mediated by VDR in osteoblast-lineage cells.