title: Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates.
abstract: Nitrogen-containing bisphosphonates are pyrophosphate analogs that have long been the preferred prescription for treating osteoporosis. Although these drugs are considered inhibitors of prenylation and are believed to exert their effects on bone resorption by disrupting the signaling pathways downstream of prenylated small GTPases, this explanation seems to be insufficient. Because other classes of prenylation inhibitors have recently emerged as potential antiviral therapeutic agents, we first investigated here the effects of bisphosphonates on simian virus 40 and adenovirus infections and, to our surprise, found that viral infections are suppressed by bisphosphonates through a prenylation-independent pathway. By in-house affinity-capture techniques, dynamin-2 was identified as a new molecular target of bisphosphonates. We present evidence that certain bisphosphonates block endocytosis of adenovirus and a model substrate by inhibiting GTPase activity of dynamin-2. Hence, this study has uncovered a previously unknown mechanism of action of bisphosphonates and offers potential novel use for these drugs.
authors.affiliation: Integrated Research Institute, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama 226-8503, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Masaike
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takagi
authors.forename: Masataka
authors.initials: M
authors.lastname: Hirota
authors.forename: Joe
authors.initials: J
authors.lastname: Yamada
authors.forename: Satoru
authors.initials: S
authors.lastname: Ishihara
authors.forename: Tetsu M C
authors.initials: TM
authors.lastname: Yung
authors.forename: Takamasa
authors.initials: T
authors.lastname: Inoue
authors.forename: Chika
authors.initials: C
authors.lastname: Sawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sagara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kabe
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D004164:Diphosphonates / Q000008:administration & dosage* / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000639:trends; D034285:Dynamin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010024:Osteoporosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D034285:Dynamin II