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Endocrinology Vol. 142, No. 12 5332-5341
Copyright © 2001 by The Endocrine Society

PTH-CALCITONIN-VITAMIN D-BONE

Aberrant Growth Plate Development in VDR/RXR{gamma} Double Null Mutant Mice

Naoko Yagishita1, Yoko Yamamoto1, Tatsuya Yoshizawa1, Keisuke Sekine, Yoshikatsu Uematsu, Hisashi Murayama, Yumiko Nagai, Wojciech Krezel, Pierre Chambon, Toshio Matsumoto and Shigeaki Kato

Institute of Molecular and Cellular Biosciences, University of Tokyo (N.Y., Y.Y., T.Y., K.S., Y.U., S.K.), Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Biomedical Research Laboratories, Kureha Chemical Industry Co. Ltd. (H.M., Y.N.), Hyakunin-cho, Shinjuku-ku, Tokyo 169-8503, Japan; Institut de Genetique et de Biologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique/INSERM/Université Louis Pasteur/College de France (W.K., P.C.), 67404 Illkirch, Strasbourg, France; First Department of Internal Medicine, University of Tokushima (T.M.), Tokushima 770-8503; and CREST, Japan Science and Technology (S.K.), Kawaguchi, Saitama 332-0012, Japan

Address all correspondence and requests for reprints to: Dr. S. Kato, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. E-mail: uskato{at}mail.ecc

VDR forms heterodimers with one of three RXRs, RXR{alpha}, RXRß, and RXR{gamma}, and it is thought that RXR ligands can also modulate the trans-activation function of VDR/RXR heterodimers. In the present study we generated VDR/RXR{gamma} double null mutant mice to examine the convergent actions of vitamin D and vitamin A signaling and to explore the possibility of a functionally redundant VDR. Although RXR{gamma}-/- mice exhibited no overt abnormalities, VDR-/-/RXR{gamma}-/- mice appeared similar to VDR-/- mice, showing features typical of vitamin D-dependent rickets type II, including growth retardation, impaired bone formation, hypocalcemia, and alopecia. However, compared to VDR-/- mice, growth plate development in VDR-/-/RXR{gamma}-/- mutant mice was more severely impaired. Normalizing mineral ion homeostasis through dietary supplementation with high calcium and phosphorous effectively prevented rachitic abnormalities, except for disarranged growth plates in VDR-/-/RXR{gamma}-/- mutant mice, and alopecia in both VDR-/- and VDR-/-/RXR{gamma}-/- mutant mice. Histological analysis of VDR-/-/RXR{gamma}-/- growth plates revealed that development of the hypertrophic chondrocytes was selectively impaired. Thus, our findings indicated that the combined actions of VDR- and RXR{gamma}-mediated signals are essential for the normal development of growth plate chondrocytes, and raised the possibility that a functionally redundant VDR is present on chondrocytes as a heterodimer with RXR{gamma}.




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