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KMID : 0811720030070000178
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Korean Journal of Physiology & Pharmacology
2003 Volume.7 No. 0 p.178 ~ p.0
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Bumetanide, the Specific Inhibitor of Na-K-Cl Cotransporter, Inhibits 1a,25-dihydroxyvitamin D3-induced Osteoclastogenesis in Mouse Coculture System
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Lee Hyun-Ah
Jeong Hyun-Joo
Kim Eun-Young
Nam Mi-Young
Yu Yoon-Jeong
Seo Jeong-Taeg
Shin Dong-Min
Ohk Seung-Ho
Lee Syng-Ill
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Abstract
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Na/K/Cl cotransporter (NKCC1) is responsible for ion transport across the secretory and absorptive epithelia, the regulation of cell volume, and possibly the modulation of cell growth and development. A variety of cells including osteoblasts contain this cotransporter. In this study, the physiological role of NKCC1 in osteoclastogenesis was exploited in a co-culture system. Bumetanide, a specific inhibitor of NKCC1, reduced the number of TRAP positive multinucleated cells. Exposure of osteoblastic cells to 1 mM of bumetanide reduced RANKL mRNA expression by 10 nM 1a, 25 (OH)2D3, in a dose-dependent manner. The expression of RANKL was decreased with the increase of bumetanide concentration, while the expression of OPG mRNA, was increased in the presence of bumetanide. These results imply that bumetanide inhibits osteoclast differentiation by reducing RANKL/OPG ratio in osteoblastic cells. However, no significant difference in M-CSF mRNA expression was observed in the presence of bumetanide. Also, we found that the phosphorylation of c-Jun NH2-terminal kinase (JNK), which regulates the activity of various transcriptional factors, was reduced by bumetanide. Conclusively, these findings suggest that NKCC1 in osteoblast has a pivotal role in 1a, 25(OH)2D3-induced osteoclastogenesis via in part the phosphorylation of JNK.
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KEYWORD
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NKCC1, bumetanide, osteoclast, RANKL, OPG, JNK
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