TY - JOUR
T1 - Improvement of impaired calcium and skeletal homeostasis in vitamin D receptor knockout mice by a high dose of calcitriol and maxacalcitol
AU - Shiizaki, Kazuhiro
AU - Hatamura, Ikuji
AU - Imazeki, Ikuo
AU - Moriguchi, Yoshiyuki
AU - Sakaguchi, Toshifumi
AU - Saji, Fumie
AU - Nakazawa, Eiko
AU - Kato, Shigeaki
AU - Akizawa, Tadao
AU - Kusano, Eiji
N1 - Funding Information:
This study was supported by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. Parts of this work were presented at the Annual Meeting of the European Renal Association-European Dialysis and Transplant Association, Barcelona, Spain, 2007, the American Society for Bone and Mineral Research, Honolulu, HI, USA 2007, and the American Society of Nephrology, San Francisco, CA, USA, 2007, and in three abstracts: Nephrol Dial Transplant 22: vi 173, 2007; J Bone Miner Res 22: S401, 2007; and J Am Soc Nephrol 18: 527A, 2007.
PY - 2009/11
Y1 - 2009/11
N2 - Vitamin D plays a major role in mineral and skeletal homeostasis through interaction with the nuclear vitamin D receptor (VDR) of target cells. Recent reports have indicated that some cellular effects of vitamin D may occur via alternative signaling pathways, but concrete evidence for mineral homeostasis has not been shown in vivo. To investigate this issue, the actions of calcitriol (1,25D) and maxacalcitol (OCT), which were developed for treatment of uremia-induced secondary hyperparathyroidism, were analyzed in VDR knockout (VDR-/-) mice. The VDR-/- mice were fed a rescue diet immediately after weaning. 1,25D, OCT or a control solution was administered intraperitoneally to these mice three times a week for eight weeks. Biological markers and bone growth were measured and bone histomorphometric analysis of the calcein-labeled tibia was performed 24 h after the final administration. Significantly higher levels of serum Ca2+ were observed in 1,25D- and OCT-treated mice, but the serum parathyroid hormone level was unchanged by both agents. Impaired bone growth, enlarged and distorted cartilaginous growth plates, morphological abnormalities of cancellous and cortical bones; a morbid osteoid increase, lack of calcein labeling, and thinning of cortical bone, were all significantly improved by 1,25D and OCT. The significance of these effects was confirmed by bone histomorphometrical analysis. Upregulation of the calbindin D9k mRNA expression level in the duodenum may explain these findings, since this protein is a major modulator of Ca transport in the small intestine. We conclude that 1,25D and OCT both at a high dose exert significant effects on Ca and skeletal homeostasis with the principal improvement of Ca status in VDR-/- mice, and some of these effects may occur through an alternative vitamin D signaling pathway.
AB - Vitamin D plays a major role in mineral and skeletal homeostasis through interaction with the nuclear vitamin D receptor (VDR) of target cells. Recent reports have indicated that some cellular effects of vitamin D may occur via alternative signaling pathways, but concrete evidence for mineral homeostasis has not been shown in vivo. To investigate this issue, the actions of calcitriol (1,25D) and maxacalcitol (OCT), which were developed for treatment of uremia-induced secondary hyperparathyroidism, were analyzed in VDR knockout (VDR-/-) mice. The VDR-/- mice were fed a rescue diet immediately after weaning. 1,25D, OCT or a control solution was administered intraperitoneally to these mice three times a week for eight weeks. Biological markers and bone growth were measured and bone histomorphometric analysis of the calcein-labeled tibia was performed 24 h after the final administration. Significantly higher levels of serum Ca2+ were observed in 1,25D- and OCT-treated mice, but the serum parathyroid hormone level was unchanged by both agents. Impaired bone growth, enlarged and distorted cartilaginous growth plates, morphological abnormalities of cancellous and cortical bones; a morbid osteoid increase, lack of calcein labeling, and thinning of cortical bone, were all significantly improved by 1,25D and OCT. The significance of these effects was confirmed by bone histomorphometrical analysis. Upregulation of the calbindin D9k mRNA expression level in the duodenum may explain these findings, since this protein is a major modulator of Ca transport in the small intestine. We conclude that 1,25D and OCT both at a high dose exert significant effects on Ca and skeletal homeostasis with the principal improvement of Ca status in VDR-/- mice, and some of these effects may occur through an alternative vitamin D signaling pathway.
KW - Bone histomorphometry
KW - Knock-out
KW - Rickets
KW - Signaling pathway
KW - Vitamin D receptor
UR - http://www.scopus.com/inward/record.url?scp=70349276695&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349276695&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2009.07.013
DO - 10.1016/j.bone.2009.07.013
M3 - Article
C2 - 19631778
AN - SCOPUS:70349276695
SN - 8756-3282
VL - 45
SP - 964
EP - 971
JO - Bone
JF - Bone
IS - 5
ER -