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A novel inhibitory mechanism of nitrogen-containing bisphosphonate on the activity of Cl- extrusion in osteoclasts.
Ohgi K
,
Kajiya H
,
Okamoto F
,
Nagaoka Y
,
Onitsuka T
,
Nagai A
,
Sakagami R
,
Okabe K
.
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Nitrogen-containing bisphosphonates have been well known to be inhibited farnesyl diphosphate synthase (FDPS), an enzyme in mevalonic acid metabolism, resulting in disturbance in polymerization of cytoskeleton structure in bone resorption and promotion of apoptosis in mature osteoclasts. Although bisphosphonates have been reported to activate ion transporters in native epithelium and Xenopus oocytes, little is known whether bisphosphonates affect acid hydrochronic acid extrusion in osteoclasts during bone resorption. The aim of this study was to determine the role of bisphosphonates on inhibition of hydrochronic acid extrusion in osteoclasts. Effects of zoledronic acid, a nitrogen-containing bisphosphonate, on the Cl(-) current activated by extracellular acidification were examined in two types of osteoclasts derived from RAW264.7 cells and mouse bone marrow macrophages (BMMs). Extracellular acidification induced outwardly rectifying Cl(-) currents in mouse osteoclasts. Zoledronic acid dose-dependently inhibited the acid-activated Cl(-) current. The non-nitrogen bisphosphonate etidronic acid had no effect on the acid-activated Cl(-) current. Tetracycline-induced FDPS silencing caused a significant decrease in the Cl(-) current. The inhibitor of geranylgeranyl transferase suppressed the Cl(-) current. By contrast, the inhibitory action of zoledronic acid was rescued by addition of geranylgeranyl acid, a derivative of mevalonic acid. The activity of acid-activated Cl(-) currents was dependent on expression of ClC-7 during osteoclastogenesis. These results suggest that nitrogen-containing bisphosphonates suppress the activity of osteoclastic acid-activated Cl(-) currents through FDPS inhibition, suggesting the inhibition of Cl(-) extrusion activity.
Amin,
1-Hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphonic acid as a potent inhibitor of squalene synthase.
1996, Pubmed
Amin,
1-Hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphonic acid as a potent inhibitor of squalene synthase.
1996,
Pubmed
Amin,
Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis.
1992,
Pubmed
Auzanneau,
A Novel voltage-dependent chloride current activated by extracellular acidic pH in cultured rat Sertoli cells.
2003,
Pubmed
,
Xenbase
Blair,
Osteoclastic bone resorption by a polarized vacuolar proton pump.
1989,
Pubmed
Bénichou,
Mapping of autosomal dominant osteopetrosis type II (Albers-Schönberg disease) to chromosome 16p13.3.
2001,
Pubmed
Caraglia,
Isoprenylation of intracellular proteins as a new target for the therapy of human neoplasms: preclinical and clinical implications.
2005,
Pubmed
Casey,
Mechanisms of protein prenylation and role in G protein function.
1995,
Pubmed
Costa,
The Arabidopsis central vacuole as an expression system for intracellular transporters: functional characterization of the Cl-/H+ exchanger CLC-7.
2012,
Pubmed
,
Xenbase
Coxon,
Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298.
2000,
Pubmed
Delmas,
The management of Paget's disease of bone.
1997,
Pubmed
Diewald,
Activation by acidic pH of CLC-7 expressed in oocytes from Xenopus laevis.
2002,
Pubmed
,
Xenbase
Dobrucali,
Physiological and morphological effects of alendronate on rabbit esophageal epithelium.
2002,
Pubmed
Dunford,
Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates.
2001,
Pubmed
Fisher,
Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro.
1999,
Pubmed
Fleisch,
Bisphosphonates: mechanisms of action.
1998,
Pubmed
Forgac,
Structure and function of vacuolar class of ATP-driven proton pumps.
1989,
Pubmed
Gibbs,
Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic.
1994,
Pubmed
Hasmim,
Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation-dependent signaling pathways.
2007,
Pubmed
Hughes,
Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo.
1995,
Pubmed
Jilka,
Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption.
1998,
Pubmed
Kajiya,
Characteristics of ClC7 Cl- channels and their inhibition in mutant (G215R) associated with autosomal dominant osteopetrosis type II in native osteoclasts and hClcn7 gene-expressing cells.
2009,
Pubmed
Karsdal,
Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption.
2005,
Pubmed
Kelly,
Outwardly rectifying chloride current in rabbit osteoclasts is activated by hyposmotic stimulation.
1994,
Pubmed
Kornak,
Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man.
2001,
Pubmed
Leisle,
ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity.
2011,
Pubmed
Liberman,
Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group.
1995,
Pubmed
Luckman,
Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation: evidence from structure-activity relationships in J774 macrophages.
1998,
Pubmed
Luckman,
Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras.
1998,
Pubmed
Monier-Faugere,
Intermittent and continuous administration of the bisphosphonate ibandronate in ovariohysterectomized beagle dogs: effects on bone morphometry and mineral properties.
1999,
Pubmed
Nobles,
Extracellular acidification elicits a chloride current that shares characteristics with ICl(swell).
2004,
Pubmed
Ohgi,
Antibodies against ClC7 inhibit extracellular acidification-induced Cl⁻ currents and bone resorption activity in mouse osteoclasts.
2011,
Pubmed
Okamoto,
Prostaglandin E2 activates outwardly rectifying Cl(-) channels via a cAMP-dependent pathway and reduces cell motility in rat osteoclasts.
2004,
Pubmed
Parfitt,
A new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates.
1996,
Pubmed
Rogers,
New insights into the molecular mechanisms of action of bisphosphonates.
2003,
Pubmed
Rogers,
Cellular and molecular mechanisms of action of bisphosphonates.
2000,
Pubmed
Russell,
Bisphosphonates: from the laboratory to the clinic and back again.
1999,
Pubmed
Sabirov,
Extra- and intracellular proton-binding sites of volume-regulated anion channels.
2000,
Pubmed
Schaller,
The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in ovariectomized rats without changing bone formation.
2004,
Pubmed
Seabra,
Prenylation assays for small GTPases.
1998,
Pubmed
Shao,
Bisphosphonates stimulate an endogenous nonselective cation channel in Xenopus oocytes: potential mechanism of action.
2005,
Pubmed
,
Xenbase
Shen,
Effects of lovastatin on trafficking of cystic fibrosis transmembrane conductance regulator in human tracheal epithelium.
1995,
Pubmed
Shi,
Simvastatin inhibits acidic extracellular pH-activated, outward rectifying chloride currents in RAW264.7 monocytic-macrophage and human peripheral monocytes.
2009,
Pubmed
Yamamoto,
Acidic extracellular pH-activated outwardly rectifying chloride current in mammalian cardiac myocytes.
2006,
Pubmed
Zhang,
Influence of metal ions on substrate binding and catalytic activity of mammalian protein geranylgeranyltransferase type-I.
1996,
Pubmed
van Beek,
Nitrogen-containing bisphosphonates inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo.
1999,
Pubmed
van beek,
The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates.
1999,
Pubmed
