Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates

Yuka Masaike, Takeshi Takagi, Masataka Hirota, Joe Yamada, Satoru Ishihara, Tetsu M C Yung, Takamasa Inoue, Chika Sawa, Hiroshi Sagara, Satoshi Sakamoto, Yasuaki Kabe, Yasuyuki Takahashi, Yuki Yamaguchi, Hiroshi Handa

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)262-269
Number of pages8
JournalMolecular Pharmacology
Volume77
Issue number2
DOIs
Publication statusPublished - 2010 Feb
Externally publishedYes

Fingerprint

Dynamin II
Diphosphonates
Endocytosis
Osteoporosis
Prenylation
Pharmaceutical Preparations
Virus Diseases
Adenoviridae Infections
Simian virus 40
Monomeric GTP-Binding Proteins
GTP Phosphohydrolases
Bone Resorption
Adenoviridae
Antiviral Agents
Prescriptions
Nitrogen

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Masaike, Y., Takagi, T., Hirota, M., Yamada, J., Ishihara, S., Yung, T. M. C., ... Handa, H. (2010). Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates. Molecular Pharmacology, 77(2), 262-269. https://doi.org/10.1124/mol.109.059006

Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates. / 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.

In: Molecular Pharmacology, Vol. 77, No. 2, 02.2010, p. 262-269.

Research output: Contribution to journalArticle

Masaike, Y, Takagi, T, Hirota, M, Yamada, J, Ishihara, S, Yung, TMC, Inoue, T, Sawa, C, Sagara, H, Sakamoto, S, Kabe, Y, Takahashi, Y, Yamaguchi, Y & Handa, H 2010, 'Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates', Molecular Pharmacology, vol. 77, no. 2, pp. 262-269. https://doi.org/10.1124/mol.109.059006
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. / Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates. In: Molecular Pharmacology. 2010 ; Vol. 77, No. 2. pp. 262-269.
@article{bb6427aee06e409da2d8be6fdd2e1e54,
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.",
author = "Yuka Masaike and Takeshi Takagi and Masataka Hirota and Joe Yamada and Satoru Ishihara and Yung, {Tetsu M C} and Takamasa Inoue and Chika Sawa and Hiroshi Sagara and Satoshi Sakamoto and Yasuaki Kabe and Yasuyuki Takahashi and Yuki Yamaguchi and Hiroshi Handa",
year = "2010",
month = "2",
doi = "10.1124/mol.109.059006",
language = "English",
volume = "77",
pages = "262--269",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates

AU - Masaike, Yuka

AU - Takagi, Takeshi

AU - Hirota, Masataka

AU - Yamada, Joe

AU - Ishihara, Satoru

AU - Yung, Tetsu M C

AU - Inoue, Takamasa

AU - Sawa, Chika

AU - Sagara, Hiroshi

AU - Sakamoto, Satoshi

AU - Kabe, Yasuaki

AU - Takahashi, Yasuyuki

AU - Yamaguchi, Yuki

AU - Handa, Hiroshi

PY - 2010/2

Y1 - 2010/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=74549131774&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=74549131774&partnerID=8YFLogxK

U2 - 10.1124/mol.109.059006

DO - 10.1124/mol.109.059006

M3 - Article

C2 - 19903825

AN - SCOPUS:74549131774

VL - 77

SP - 262

EP - 269

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 2

ER -