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

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...

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Bibliographic Details
Published in:The Journal of membrane biology 2015-02, Vol.248 (1), p.103-115
Main Authors: Wu, Sheng-Nan, Huang, Yan-Ming, Liao, Yu-Kai
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Biomedical and Life Sciences
Cell adhesion & migration
Cell Line
Cell Movement - drug effects
Diphosphonates - pharmacology
Human Physiology
Intermediate-Conductance Calcium-Activated Potassium Channels - metabolism
Ions
Life Sciences
Membrane Potentials - drug effects
Membranes
Mice
Nitrogen
Osteoclasts - drug effects
Osteoclasts - metabolism
Potassium
Potassium - metabolism
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Summary: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 IC 50 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 Ca 2+ -activated K + (IK Ca ) 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 IK Ca channels; however, it did reduce channel activity. Iban-induced inhibition of IK Ca channels was voltage-dependent. As IK Ca -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 IK Ca channels would be an important mechanism underlying its actions on the functional activity of osteoclasts occurring in vivo.
ISSN:0022-2631
1432-1424
DOI:10.1007/s00232-014-9747-8