Oral

[O3-E-AM2-05] The vitamin D receptor in osteoblasts but not parathyroid hormone is crucial for ectopic calcification induced by the proresorptive activity of 1,25(OH)₂D₃

〇Yuko Nakamichi^1,2, Ziyang Liu², Zhifeng He¹, Naoyuki Takahashi^1,2, Nobuyuki Udagawa^1,2,3 (1. Inst Oral Sci, Matsumoto Dent Univ, 2. Grad Sch Oral Med, Matsumoto Dent Univ, 3. Dept Biochem, Matsumoto Dent Univ)

Keywords:骨芽細胞、ビタミンD受容体、軟組織石灰化

VDR is expressed most abundantly in osteoblasts and osteocytes (osteoblastic cells) in bone, and regulates bone resorption and calcium (Ca) homeostasis in concert with PTH. We reported that near-physiological doses of vitamin D analogs suppressed bone resorption through VDR in osteoblastic cells (JBMR 2017). We also reported that supra-physiological doses of 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] increased bone resorption and serum Ca levels via VDR in osteoblastic cells (Endocrinology 2020). The present study demonstrated that the latter, a proresorptive dose of 1,25(OH)₂D₃, induced soft tissue calcification through VDR in osteoblastic cells. Excess amounts of vitamin D affect various organs and induce ectopic calcification, with increases in bone resorption and serum Ca levels. Such a wide range of symptoms is called as hypervitaminosis D, which is caused by not only too much intake of vitamin D but also diseases that produce 1,25(OH)₂D₃ ectopically. To clarify a biological process hierarchy in hypervitaminosis D, a proresorptive dose of 1,25(OH)₂D₃ was administered to wild-type mice whose bone resorption was suppressed with neutralizing anti-RANKL antibody. Proresorptive doses of 1,25(OH)₂D₃ induced calcification of the aortas, lungs, and kidneys, and decreased serum PTH levels in the 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)₂D₃, but inhibited soft tissue calcification induced by 1,25(OH)₂D₃. 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)₂D₃, but inhibited 1,25(OH)₂D₃-induced calcification of soft tissues. These data suggest that bone resorption induced by VDR signaling in osteoblastic cells is crucial for the pathogenesis of hypervitaminosis D, but PTH is not relevant to it. These findings indicate that the use of bone resorption inhibitors is a treatment option not only for patients with hypervitaminosis D but also for patients with other diseases having complications of hypercalcemia and ectopic calcification.