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Effects of Ibandronate Sodium, a Nitrogen-Containing Bisphosphonate, on Intermediate-Conductance Calcium-Activated Potassium Channels in Osteoclast Precursor Cells (RAW 264.7)

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Abstract

Ibanonate sodium (Iban), a nitrogen-containing bisphosphonate, is recognized to reduce skeletal complications through an inhibition of osteoclast-mediated bone resorption. However, how this drug interacts with ion channels in osteoclasts and creates anti-osteoclastic activity remains largely unclear. In this study, we investigated the possible effects of Iban and other related compounds on ionic currents in the osteoclast precursor RAW 264.7 cells. Iban suppressed the amplitude of whole-cell K+ currents (I K) in a concentration-dependent manner with an IC50 value of 28.9 μM. The I K amplitude was sensitive to block by TRAM-34 and Iban-mediated inhibition of I K was reversed by further addition of DCEBIO, an activator of intermediate-conductance Ca2+-activated K+ (IKCa) channels. Intracellular dialysis with Iban diminished I K amplitude and further addition of ionomycin reversed its inhibition. In 17β-estradiol-treated cells, Iban-mediated inhibition of I K remained effective. In cell-attached current recordings, Iban applied to bath did not modify single-channel conductance of IKCa channels; however, it did reduce channel activity. Iban-induced inhibition of IKCa channels was voltage-dependent. As IKCa-channel activity was suppressed by KN-93, subsequent addition of Iban did not further decrease the channel open probability. Iban could not exert any effect on inwardly rectifying K+ current in RAW 264.7 cells. Under current-clamp recordings, Iban depolarized the membrane of RAW 264.7 cells and DCEBIO reversed Iban-induced depolarization. Iban also suppressed lipopolysaccharide-stimulated migration of RAW 264.7 cells in a concentration-dependent manner. Therefore, the inhibition by Iban of IKCa channels would be an important mechanism underlying its actions on the functional activity of osteoclasts occurring in vivo.

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Acknowledgments

Part of the research leading to the present results was aided by a grant from the National Science Council (NSC-101-2320-B-006-009), Taiwan, through a contract awarded to S.N.W. and from the Aim for the Top University Project, National Cheng Kung University, Tainan City, Taiwan. The authors are grateful to Ming-Chun Hsu for her technical assistance in this work.

Conflict of interest

No conflicts of interest, financial or otherwise, are declared by the author(s).

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Authors and Affiliations

  1. Department of Physiology, National Cheng Kung University Medical College, No. 1 University Road, Tainan City, 70101, Taiwan

    Sheng-Nan Wu, Yan-Ming Huang & Yu-Kai Liao

  2. Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan City, Taiwan

    Sheng-Nan Wu

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  1. Sheng-Nan Wu
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  2. Yan-Ming Huang
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Correspondence to Sheng-Nan Wu.

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Wu, SN., Huang, YM. & Liao, YK. Effects of Ibandronate Sodium, a Nitrogen-Containing Bisphosphonate, on Intermediate-Conductance Calcium-Activated Potassium Channels in Osteoclast Precursor Cells (RAW 264.7). J Membrane Biol 248, 103–115 (2015). https://doi.org/10.1007/s00232-014-9747-8

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