Identification of Dynamin-2-Mediated Endocytosis as a New Target of Osteoporosis Drugs, Bisphosphonates

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 downst...

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Bibliographic Details
Published in:Molecular pharmacology 2010-02, Vol.77 (2), p.262-269
Main Authors: Masaike, Yuka, Takagi, Takeshi, Hirota, Masataka, Yamada, Joe, Ishihara, Satoru, Yung, Tetsu M C, Inoue, Takamasa, Sawa, Chika, Sagara, Hiroshi, Sakamoto, Satoshi, Kabe, Yasuaki, Takahashi, Yasuyuki, Yamaguchi, Yuki, Handa, Hiroshi
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.109.059006