Improvement of impaired calcium and skeletal homeostasis in vitamin D receptor knockout mice by a high dose of calcitriol and maxacalcitol |
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Authors: | Kazuhiro Shiizaki Ikuji Hatamura Ikuo Imazeki Yoshiyuki Moriguchi Toshifumi Sakaguchi Fumie Saji Eiko Nakazawa Shigeaki Kato Tadao Akizawa Eiji Kusano |
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Affiliation: | 1. Division of Nephrology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan;2. Division of Molecular Medicine, Kansai University of Health Sciences, Kumatori 590-0482, Japan;3. Medical Section, Sendai Branch, Chugai Pharmaceutical Co., Ltd., Sendai 980-0014, Japan;4. Product Research Department, Chugai Pharmaceutical Co., Ltd., Gotenba 412-8513, Japan;5. Division of Nephrology and Blood Purification Medicine, Wakayama Medical University, Wakayama 641-0012, Japan;6. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan;7. Department of Nephrology, Showa University School of Medicine, Tokyo 142-8666, Japan;1. Clinical and Experimental Medicine and Endocrinology, KU Leuven, Herestraat 49, Box 902, 3000 Leuven, Belgium;2. Gene Expression Unit, Dept. of Molecular and Cellular Medicine, KU Leuven, Herestraat 49, Box 901, 3000 Leuven, Belgium;3. University of Tokyo Hospital, University of Tokyo, 113-8655 Tokyo, Japan;4. Soma Central Hospital, 976-0016 Fukushima, Japan;1. Laboratory for Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium;2. Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan;1. Centrum Voor Hart- en Vaatziekten, UZ Brussel, Brussels, Belgium;2. In Vivo Cellular and Molecular Imaging, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium;3. Bruker microCT, Kontich, Belgium;4. Department of Pathology, Centre Hospitalier Universitaire de Liège, Liège, Belgium;6. Laboratory of Clinical Chemistry & Radioimmunology, UZ Brussel, Brussels, Belgium;5. Department of Nuclear Medicine, UZ Brussel, Brussels, Belgium;1. Department of Orthopedics, Second Hospital Affiliated to Xi''an Jiaotong University, Xi''an 710004, Shaanxi, China;2. Department of Military Medical Training, Urumql Ethnic Cadre College, Hutubi 831200, Xinjiang, China;1. Institute of Chemistry, St. Petersburg State University, Russia;2. Institute of Macromolecular Chemistry, AS CR, Heyrovsky Sq. 2, Prague 6, Prague 162 06, Czech Republic;3. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Petersburg, Russia;4. Helmholz-Zentrum Geesthacht: Zentrum für Material und Küstenforschung GmbH, DE-21502 Geesthacht, Germany;5. North-West Federal Medical Research Centre, St. Petersburg, Russia |
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Abstract: | 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. |
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Keywords: | Bone histomorphometry Knock-out Rickets Signaling pathway Vitamin D receptor |
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