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Vol. 19, Issue 5, 1912-1921, May 2008

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Tight Junction Proteins Claudin-2 and -12 Are Critical for Vitamin D-dependent Ca²⁺ Absorption between Enterocytes

Hiroki Fujita^*,,, Kotaro Sugimoto^*,, Shuichiro Inatomi^*,, Toshihiro Maeda^*, Makoto Osanai^*, Yasushi Uchiyama, Yoko Yamamoto^||, Takuro Wada, Takashi Kojima^*, Hiroshi Yokozaki^¶, Toshihiko Yamashita, Shigeaki Kato^||, Norimasa Sawada^*, and Hideki Chiba^*

*Departments of Pathology and Orthopedic Surgery, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; Chugai Pharmaceutical Co., Ltd., Tokyo 104-8301, Japan; ^||Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan; and ^¶Division of Surgical Pathology, Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan

Submitted September 28, 2007; Revised January 14, 2008; Accepted February 8, 2008
Monitoring Editor: Asma Nusrat

Ca²⁺ is absorbed across intestinal epithelial monolayers via transcellular and paracellular pathways, and an active form of vitamin D₃, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], is known to promote intestinal Ca²⁺ absorption. However, the molecules driving the paracellular Ca²⁺ absorption and its vitamin D dependency remain obscure. Because the tight junction proteins claudins are suggested to form paracellular channels for selective ions between neighboring cells, we hypothesized that specific intestinal claudins might facilitate paracellular Ca²⁺ transport and that expression of these claudins could be induced by 1,25(OH)₂D₃. Herein, we show, by using RNA interference and overexpression strategies, that claudin-2 and claudin-12 contribute to Ca²⁺ absorption in intestinal epithelial cells. We also provide evidence showing that expression of claudins-2 and -12 is up-regulated in enterocytes in vitro and in vivo by 1,25(OH)₂D₃ through the vitamin D receptor. These findings strongly suggest that claudin-2- and/or claudin-12-based tight junctions form paracellular Ca²⁺ channels in intestinal epithelia, and they highlight a novel mechanism behind vitamin D-dependent calcium homeostasis.

These authors contributed equally to this work.

Address correspondence to: Hideki Chiba (hidchiba{at}sapmed.ac.jp)

Abbreviations used: Cldn, claudin; EBP50, ezrin/radixin/moesin-binding phosphoprotein 50; FHHNC, familial hypomagnesemia with hypercalciuria and nephrocalcinosis; KO, knockout; PCLN-1, paracellin-1; siRNA, small interfering RNA; TER, transepithelial electrical resistance.; VDR, vitamin D receptor; WT, wild type.

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