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Am J Physiol Cell Physiol 294: C693-C701, 2008. First published January 30, 2008; doi:10.1152/ajpcell.00251.2007
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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Intracellular ClC-3 chloride channels promote bone resorption in vitro through organelle acidification in mouse osteoclasts

Fujio Okamoto,1 Hiroshi Kajiya,1 Kazuko Toh,2 Shinichi Uchida,3 Momono Yoshikawa,3 Sei Sasaki,3 Mizuho A. Kido,4 Teruo Tanaka,4 and Koji Okabe1

1Department of Physiological Science and Molecular Biology and 2Department of Oral Rehabilitation, Fukuoka Dental College, Fukuoka; 3Homeostasis Medicine and Nephrology, Graduate School, Tokyo Medical and Dental University, Tokyo; and 4Department of Oral Anatomy and Cell Biology, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan

Submitted 13 June 2007 ; accepted in final form 22 January 2008

ClC-7 Cl– channels expressed in osteoclasts are important for bone resorption since it has been shown that disruption of the ClCN7 gene in mice leads to severe osteopetrosis. We have previously reported that Cl– currents recorded from mouse osteoclasts resemble those of ClC-3 Cl– channels. The aim of the present study was to determine the expression of ClC-3 channels in mouse osteoclasts and their functional role during bone resorption. We detected transcripts for both ClC-7 and ClC-3 channels in mouse osteoclasts by RT-PCR. The expression of ClC-3 was confirmed by immunocytochemical staining. Mouse osteoclasts lacking ClC-3 Cl– channels (ClC-3–/– osteoclasts) derived from ClCN3 gene-deficient mice (ClC-3–/–) showed lower bone resorption activity compared with ClC-3+/+ osteoclasts derived from wild-type mice (ClC-3+/+). Treatment of ClC-3+/+ osteoclasts with small interfering RNA (siRNA) against ClC-3 also significantly reduced bone resorption activity. Electrophysiological properties of basal and hypotonicity-induced Cl– currents in ClC-3–/– osteoclasts did not differ significantly from those in ClC-3+/+ osteoclasts. Using immunocytochemistry, ClC-3 was colocalized with lysosome-associated membrane protein 2. Using pH-sensitive dyes, organelle acidification activity in ClC-3–/– osteoclasts was weaker than in ClC-3+/+ osteoclasts. Treatment of ClC-3+/+ osteoclasts with siRNA against ClC-3 also reduced the organelle acidification activity. In conclusion, ClC-3 Cl– channels are expressed in intracellular organelles of mouse osteoclasts and contribute to osteoclastic bone resorption in vitro through organelle acidification.

knockout mice; Cl– current; lysosome-associated membrane protein; pH-sensitive dye staining


Address for reprint requests and other correspondence: F. Okamoto, Dept. of Physiological Science and Molecular Biology, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan (e-mail: fujipi{at}college.fdcnet.ac.jp)






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