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

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16 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 1
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Masaike, Y., Takagi, T., Hirota, M., Yamada, J., Ishihara, S., Yung, T. M. C., 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, 77(2), 262-269. https://doi.org/10.1124/mol.109.059006