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MBC in Press, published online ahead of print February 20, 2008
Mol. Biol. Cell 10.1091/mbc.E07-09-0973

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Submitted on September 28, 2007
Revised on January 14, 2008
Accepted on February 8, 2008

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

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

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

Monitoring Editor: Asma Nusrat

Ca2+ is absorbed across intestinal epithelial monolayers via transcellular and paracellular pathways, and an active form of vitamin D3, 1{alpha},25-dihydroxyvitamin D3 [1{alpha},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 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 by1{alpha},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{alpha},25(OH)2D3 through its receptor VDR. These findings strongly suggest that claudin-2- and/or claudin-12-based tight junctions form paracellular Ca2+ channels in intestinal epithelia, and highlight a novel mechanism behind vitamin D-dependent calcium homeostasis.

{ddagger}These authors contributed equally to this work.

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






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