Transgenic Expression of the Vitamin D Receptor Restricted to the Ileum, Cecum, and Colon of Vitamin D Receptor Knockout Mice Rescues Vitamin D Receptor−Dependent Rickets
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 it is the distal intestine where 70 -80% of the ingested calcium is absorbed. In order to test directly the role of 1,25(OH)2D3 and the vitamin D receptor (VDR) in the distal intestine, 3 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 (h)VDR under the control of the 9.5kb CDX2 promoter. Mice from one TG line (KO/TG3) showed low VDR expression in distal intestine (<50% of the levels observed in KO/TG1, KO/TG2 and WT mice). In the KO/TG mice hVDR was not expressed in duodenum, jejunum, kidney or other tissues. Growth arrest, elevated parathyroid hormone and hypocalcemia of the VDR KO mice were prevented in mice from KO/TG lines 1 and 2. µCT 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, yet less severely compared to 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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