TY - JOUR
T1 - Transgenic expression of the Vitamin D receptor restricted to the ileum, cecum, and colon of Vitamin D receptor knockout mice rescues Vitamin D receptor2dependent rickets
AU - Dhawan, Puneet
AU - Veldurthy, Vaishali
AU - Yehia, Ghassan
AU - Hsaio, Connie
AU - Porta, Angela
AU - Kim, Ki In
AU - Patel, Nishant
AU - Lieben, Liesbet
AU - Verlinden, Lieve
AU - Carmeliet, Geert
AU - Christakos, Sylvia
N1 - Funding Information:
Financial Support: This work was supported by National Institutes of Health Grants DK38961, AG-044552, and DK112365 (to S.C.). L.L, L.V., and G.C. were supported by Fund for Scientific Research Flanders Grants G.0573.13N and G0A2416N.
Publisher Copyright:
© 2017 Endocrine Society.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Although the intestine plays the major role in 1,25-dihydroxyVitamin D3 [1,25(OH)2D3] action on calcium homeostasis, the mechanisms involved remain incompletely understood. The established model of 1,25(OH)2D3-regulated intestinal calcium absorption postulates a critical role for the duodenum. However, the distal intestine is where 70% to 80% of ingested calcium is absorbed. To test directly the role of 1,25(OH)2D3 and the Vitamin D receptor (VDR) in the distal intestine, three independent knockout (KO)/transgenic (TG) lines expressing VDR exclusively in the ileum, cecum, and colon were generated by breeding VDR KO mice with TG mice expressing human VDR (hVDR) under the control of the 9.5-kb caudal type homeobox 2 promoter. Mice from one TG line (KO/TG3) showed low VDR expression in the distal intestine (<50% of the levels observed in KO/TG1, KO/TG2, and wild-type mice). In the KO/TG mice, hVDR was not expressed in the duodenum, jejunum, kidney, or other tissues. Growth arrest, elevated parathyroid hormone level, and hypocalcemia of the VDR KO mice were prevented in mice from KO/TG lines 1 and 2. Microcomputed tomography analysis revealed that the expression of hVDR in the distal intestine of KO/TG1 and KO/TG2 mice rescued the bone defects associated with systemic VDR deficiency, including growth plate abnormalities and altered trabecular and cortical parameters. KO/TG3 mice showed rickets, but less severely than VDR KO mice. These findings show that expression of VDR exclusively in the distal intestine can prevent abnormalities in calcium homeostasis and bone mineralization associated with systemic VDR deficiency.
AB - Although the intestine plays the major role in 1,25-dihydroxyVitamin D3 [1,25(OH)2D3] action on calcium homeostasis, the mechanisms involved remain incompletely understood. The established model of 1,25(OH)2D3-regulated intestinal calcium absorption postulates a critical role for the duodenum. However, the distal intestine is where 70% to 80% of ingested calcium is absorbed. To test directly the role of 1,25(OH)2D3 and the Vitamin D receptor (VDR) in the distal intestine, three independent knockout (KO)/transgenic (TG) lines expressing VDR exclusively in the ileum, cecum, and colon were generated by breeding VDR KO mice with TG mice expressing human VDR (hVDR) under the control of the 9.5-kb caudal type homeobox 2 promoter. Mice from one TG line (KO/TG3) showed low VDR expression in the distal intestine (<50% of the levels observed in KO/TG1, KO/TG2, and wild-type mice). In the KO/TG mice, hVDR was not expressed in the duodenum, jejunum, kidney, or other tissues. Growth arrest, elevated parathyroid hormone level, and hypocalcemia of the VDR KO mice were prevented in mice from KO/TG lines 1 and 2. Microcomputed tomography analysis revealed that the expression of hVDR in the distal intestine of KO/TG1 and KO/TG2 mice rescued the bone defects associated with systemic VDR deficiency, including growth plate abnormalities and altered trabecular and cortical parameters. KO/TG3 mice showed rickets, but less severely than VDR KO mice. These findings show that expression of VDR exclusively in the distal intestine can prevent abnormalities in calcium homeostasis and bone mineralization associated with systemic VDR deficiency.
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U2 - 10.1210/en.2017-00258
DO - 10.1210/en.2017-00258
M3 - Article
C2 - 28938396
AN - SCOPUS:85034422194
VL - 158
SP - 3792
EP - 3804
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 11
ER -