For the special issue on the 24th (2022) Vitamin D Workshop, Austin The vitamin D receptor in osteoblastic cells but not secreted parathyroid hormone is crucial for soft tissue calcification induced by the proresorptive activity of 1,25(OH) 2 D 3 .

The vitamin D receptor (VDR) is expressed most abundantly in osteoblasts and osteocytes (osteoblastic cells) in bone tissues and regulates bone resorption and calcium (Ca) and phosphate (P) homeostasis in association with parathyroid hormone (PTH). We previously reported that near-physiological doses of vitamin D compounds suppressed bone resorption through VDR in osteoblastic cells. We also found that supra-physiological doses of 1α,25-dihydroxyvitamin D [1,25(OH)D] induced bone resorption and hypercalcemia via VDR in osteoblastic cells. Here, we report that the latter, a proresorptive dose of 1,25(OH)D, causes soft tissue calcification through VDR in osteoblastic cells. High concentrations of vitamin D affect multiple organs and cause soft tissue calcification, with increases in bone resorption and serum Ca levels. Such a variety of symptoms is known as hypervitaminosis D, which is caused by not only high doses of vitamin D but also impaired vitamin D metabolism and diseases that produce 1,25(OH)D ectopically. To clarify the biological process hierarchy in hypervitaminosis D, a proresorptive dose of 1,25(OH)D was administered to wild-type mice in which bone resorption had been suppressed by neutralizing anti-receptor activator of NF-κB ligand (RANKL) antibody. 1,25(OH)D upregulated the serum Ca x P product, concomitantly induced calcification of the aorta, lungs, and kidneys, and downregulated serum PTH levels in control IgG-pretreated wild-type mice. Pretreatment of wild-type mice with anti-RANKL antibody did not affect the down-regulation of PTH levels by 1,25(OH)D, but inhibited the increase of the serum Ca x P product and soft tissue calcification induced by 1,25(OH)D. Consistent with the effects of anti-RANKL antibody, VDR ablation in osteoblastic cells also did not affect the down-regulation of PTH levels by 1,25(OH)D, but suppressed the 1,25(OH)D-induced increase of the serum Ca x P product and calcification of soft tissues. Taken together with our previous results, these findings suggest that bone resorption induced by VDR signaling in osteoblastic cells is critical for the pathogenesis of hypervitaminosis D, but PTH is not involved in hypervitaminosis D.