RRC ID 11017
Author Masaike Y, Takagi T, Hirota M, Yamada J, Ishihara S, Yung TM, Inoue T, Sawa C, Sagara H, Sakamoto S, Kabe Y, Takahashi Y, Yamaguchi Y, Handa H.
Title Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates.
Journal Mol Pharmacol
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.
Volume 77(2)
Pages 262-9
Published 2010-2-1
DOI 10.1124/mol.109.059006
PII mol.109.059006
PMID 19903825
MeSH Animals Bone Density Conservation Agents / administration & dosage* Bone Density Conservation Agents / pharmacology Cattle Cell Line Diphosphonates / administration & dosage* Diphosphonates / pharmacology Drug Delivery Systems* / trends Dynamin II / antagonists & inhibitors Dynamin II / physiology* Endocytosis / drug effects* Endocytosis / physiology* HeLa Cells Humans Mice Osteoporosis / drug therapy Osteoporosis / metabolism* Osteoporosis / pathology* Protein Prenylation / drug effects Protein Prenylation / physiology Signal Transduction / drug effects Signal Transduction / physiology
IF 3.664
Times Cited 16
DNA material AxCA Luc+ (RDB02453)