title: A novel inhibitory mechanism of nitrogen-containing bisphosphonate on the activity of Cl- extrusion in osteoclasts.
abstract: 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.
authors.affiliation: Department of Odontology, Fukuoka Dental College, Tamura 2-15-1, Sawara-ku, Fukuoka 8140193, Japan.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Ohgi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kajiya
authors.forename: Fujio
authors.initials: F
authors.lastname: Okamoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nagaoka
authors.forename: Tokuya
authors.initials: T
authors.lastname: Onitsuka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nagai
authors.forename: Ryuji
authors.initials: R
authors.lastname: Sakagami
authors.forename: Koji
authors.initials: K
authors.lastname: Okabe
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D002478:Cells, Cultured; D002712:Chlorides / Q000502:physiology*; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology; D020868:Gene Silencing; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009584:Nitrogen / Q000737:chemistry; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D002712:Chlorides; D004164:Diphosphonates; D004224:Diterpenes; D034741:RNA, Small Interfering; C017338:geranylgeraniol; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051228:Geranyltranstransferase; D009584:Nitrogen
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