{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:07:16Z","timestamp":1791220036820,"version":"4.1.0"},"reference-count":44,"publisher":"The Endocrine Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>VDR forms heterodimers with one of three RXRs, RXR\u03b1, RXR\u03b2, and RXR\u03b3, 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\u03b3 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\u03b3\u2212\/\u2212 mice exhibited no overt abnormalities, VDR\u2212\/\u2212\/RXR\u03b3\u2212\/\u2212 mice appeared similar to VDR\u2212\/\u2212 mice, showing features typical of vitamin D-dependent rickets type II, including growth retardation, impaired bone formation, hypocalcemia, and alopecia. However, compared to VDR\u2212\/\u2212 mice, growth plate development in VDR\u2212\/\u2212\/RXR\u03b3\u2212\/\u2212 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\u2212\/\u2212\/RXR\u03b3\u2212\/\u2212 mutant mice, and alopecia in both VDR\u2212\/\u2212 and VDR\u2212\/\u2212\/RXR\u03b3\u2212\/\u2212 mutant mice. Histological analysis of VDR\u2212\/\u2212\/RXR\u03b3\u2212\/\u2212 growth plates revealed that development of the hypertrophic chondrocytes was selectively impaired. Thus, our findings indicated that the combined actions of VDR- and RXR\u03b3-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\u03b3.<\/jats:p>","DOI":"10.1210\/endo.142.12.8544","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T16:11:14Z","timestamp":1389197474000},"page":"5332-5341","source":"Crossref","is-referenced-by-count":39,"title":["Aberrant Growth Plate Development in VDR\/RXR\u03b3 Double Null Mutant Mice"],"prefix":"10.1210","volume":"142","author":[{"given":"Naoko","family":"Yagishita","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Yoshizawa","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Sekine","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikatsu","family":"Uematsu","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Murayama","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories, Kureha Chemical Industry Co. 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770-8503"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeaki","family":"Kato","sequence":"additional","affiliation":[{"name":"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"},{"name":"CREST, Japan Science and Technology (S.K.), Kawaguchi, Saitama 332-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071620301941500_R1","first-page":"719","article-title":"Newly identified actions of the vitamin D endocrine system.","volume":"13","author":"Walters","year":"1992","journal-title":"Endocr Rev"},{"key":"2020071620301941500_R2","first-page":"200","article-title":"Structure-function relationships in the vitamin D endocrine system.","volume":"16","author":"Bouillon","year":"1995","journal-title":"Endocr Rev"},{"key":"2020071620301941500_R3","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1210\/edrv-3-4-331","article-title":"The vitamin D endocrine system:steroid metabolism, hormone receptors, and biological response (calcium binding proteins).","volume":"3","author":"Norman","year":"1982","journal-title":"Endocr Rev"},{"key":"2020071620301941500_R4","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/978-1-4684-5101-6_24","article-title":"The metabolism and functions of vitamin D.","volume":"196","author":"DeLuca","year":"1986","journal-title":"Adv Exp Med Biol"},{"key":"2020071620301941500_R5","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1359\/jbmr.1998.13.3.325","article-title":"The nuclear vitamin D receptor: biological and molecular regulatory properties revealed.","volume":"13","author":"Haussler","year":"1998","journal-title":"J Bone Miner Res"},{"key":"2020071620301941500_R6","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1128\/MCB.19.2.1049","article-title":"Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog.","volume":"19","author":"Takeyama","year":"1999","journal-title":"Mol Cell Biol"},{"key":"2020071620301941500_R7","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/0092-8674(95)90199-X","article-title":"The nuclear receptor superfamily: the second decade.","volume":"83","author":"Mangelsdorf","year":"1995","journal-title":"Cell"},{"key":"2020071620301941500_R8","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S0092-8674(00)80708-4","article-title":"Increasing the complexity of coactivation in nuclear receptor signaling.","volume":"97","author":"Freedman","year":"1999","journal-title":"Cell"},{"key":"2020071620301941500_R9","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.1128\/MCB.14.5.3329","article-title":"Ligand modulates the conversion of DNA-bound vitamin D3 receptor (VDR) homodimers into VDR-retinoid X receptor heterodimers.","volume":"14","author":"Cheskis","year":"1994","journal-title":"Mol Cell Biol"},{"key":"2020071620301941500_R10","doi-asserted-by":"crossref","first-page":"3393","DOI":"10.1128\/MCB.16.7.3393","article-title":"Intron retention generates a novel isoform of the murine vitamin D receptor that acts in a dominant negative way on the vitamin D signaling pathway.","volume":"16","author":"Ebihara","year":"1996","journal-title":"Mol Cell Biol"},{"key":"2020071620301941500_R11","doi-asserted-by":"crossref","first-page":"9831","DOI":"10.1073\/pnas.94.18.9831","article-title":"Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia.","volume":"94","author":"Li","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071620301941500_R12","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/ng0897-391","article-title":"Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning.","volume":"16","author":"Yoshizawa","year":"1997","journal-title":"Nat Genet"},{"key":"2020071620301941500_R13","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1126\/science.2849209","article-title":"Point mutations in the human vitamin D receptor associated with hypocalcemic rickets.","volume":"242","author":"Hughes","year":"1988","journal-title":"Science"},{"key":"2020071620301941500_R14","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/jbmr.5650060309","article-title":"Normocalcemia without hyperparathyroidism in vitamin D-deficient rats.","volume":"6","author":"Kollenkirchen","year":"1991","journal-title":"J Bone Miner Res"},{"key":"2020071620301941500_R15","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1126\/science.277.5333.1827","article-title":"25-Hydroxyvitamin D3 1\u03b1-hydroxylase and vitamin D synthesis.","volume":"277","author":"Takeyama","year":"1997","journal-title":"Science"},{"key":"2020071620301941500_R16","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/00041552-199807000-00005","article-title":"The importance of 25-hydroxyvitamin D3 1\u03b1-hydroxylase gene in vitamin D- dependent rickets.","volume":"7","author":"Kato","year":"1998","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"2020071620301941500_R17","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/0092-8674(95)90202-3","article-title":"Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real 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mice.","volume":"140","author":"Takeda","year":"1999","journal-title":"Endocrinology"},{"key":"2020071620301941500_R26","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1210\/endo-123-5-2600","article-title":"Osteoblastic cells are involved in osteoclast formation.","volume":"123","author":"Takahashi","year":"1988","journal-title":"Endocrinology"},{"key":"2020071620301941500_R27","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/35036595","article-title":"Skin abnormalities generated by temporally controlled RXR\u03b1 mutations in mouse epidermis.","volume":"407","author":"Li","year":"2000","journal-title":"Nature"},{"key":"2020071620301941500_R28","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1007\/BF02557684","article-title":"1\u03b1,25-dihydroxyvitamin D3 receptors and their action in embryonic chick chondrocytes.","volume":"37","author":"Suda","year":"1985","journal-title":"Calcif Tissue 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olivaceus.","volume":"270","author":"Suzuki","year":"2000","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071620301941500_R38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0092-8674(00)00097-0","article-title":"Don\u2019t know much bile-ology.","volume":"103","author":"Chawla","year":"2000","journal-title":"Cell"},{"key":"2020071620301941500_R39","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1101\/gad.13.23.3037","article-title":"The genetic transformation of bone biology.","volume":"13","author":"Karsenty","year":"1999","journal-title":"Genes Dev"},{"key":"2020071620301941500_R40","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1046\/j.1523-1755.2000.00081.x","article-title":"The family of bone morphogenetic proteins.","volume":"57","author":"Ducy","year":"2000","journal-title":"Kidney 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