Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras

S P Luckman, Michael David Hughes, Fraser Coxon, R. Graham G. Russell, Michael John Rogers

Research output: Contribution to journalArticle

979 Citations (Scopus)

Abstract

Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of metabolic bone diseases. Although the molecular targets of bisphosphonates have not been identified, these compounds inhibit bone resorption by mechanisms that can lead to osteoclast apoptosis. Bisphosphonates also induce apoptosis in mouse J774 macrophages in vitro, probably by the same mechanisms that lead to osteoclast apoptosis. We have found that, in J774 macrophages, nitrogen-containing bisphosphonates (such as alendronate, ibandronate, and risedronate) inhibit post-translational modification (prenylation) of proteins, including the GTP-binding protein Ras, with farnesyl or geranylgeranyl isoprenoid groups. Clodronate did not inhibit protein prenylation. Mevastatin, an inhibitor of 3-hydroxy-3-methylglutatyl (HMG)-CoA reductase and hence the biosynthetic pathway required for the production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, also caused apoptosis in J774 macrophages and murine osteoclasts in vitro. Furthermore, alendronate-induced apoptosis, like mevastatin-induced apoptosis, could be suppressed in J774 cells by the addition of farnesyl pyrophosphate or geranylgeranyl pyrophosphate, while the effect of alendronate on osteoclast number and bone resorption in murine calvariae in vitro could be overcome by the addition of mevalonic acid. These observations suggest that nitrogen-containing bisphosphonate drugs cause apoptosis following inhibition of post-translational prenylation of proteins such as Ras. It is likely that these potent antiresorptive bisphosphonates also inhibit bone resorption by preventing protein prenylation in osteoclasts and that enzymes of the mevalonate pathway or prenyl protein transferases are the molecular targets of the nitrogen-containing bisphosphonates. Furthermore, the data support the view that clodronate acts by a different mechanism.
Original languageEnglish
Pages (from-to)581-589
Number of pages9
JournalJournal of Bone and Mineral Research
Volume13
Issue number4
DOIs
Publication statusPublished - 1 Apr 1998

Fingerprint

Prenylation
Mevalonic Acid
Diphosphonates
GTP-Binding Proteins
Nitrogen
Osteoclasts
Apoptosis
Protein Prenylation
Alendronate
Bone Resorption
Clodronic Acid
Macrophages
Bone Density Conservation Agents
Metabolic Bone Diseases
Biosynthetic Pathways
Terpenes
Coenzyme A
Post Translational Protein Processing
Transferases
Skull

Keywords

  • Alendronate
  • Animals
  • Apoptosis
  • Bone Resorption
  • Cells, Cultured
  • Clodronic Acid
  • Diphosphonates
  • Enzyme Inhibitors
  • Etidronic Acid
  • Hydroxymethylglutaryl CoA Reductases
  • Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent
  • Lovastatin
  • Macrophages
  • Mevalonic Acid
  • Mice
  • Osteoclasts
  • Protein Prenylation
  • Protein Processing, Post-Translational
  • Structure-Activity Relationship
  • ras Proteins

Cite this

Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. / Luckman, S P; Hughes, Michael David; Coxon, Fraser; Russell, R. Graham G. ; Rogers, Michael John.

In: Journal of Bone and Mineral Research, Vol. 13, No. 4, 01.04.1998, p. 581-589.

Research output: Contribution to journalArticle

Luckman, S P ; Hughes, Michael David ; Coxon, Fraser ; Russell, R. Graham G. ; Rogers, Michael John. / Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. In: Journal of Bone and Mineral Research. 1998 ; Vol. 13, No. 4. pp. 581-589.
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AB - Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of metabolic bone diseases. Although the molecular targets of bisphosphonates have not been identified, these compounds inhibit bone resorption by mechanisms that can lead to osteoclast apoptosis. Bisphosphonates also induce apoptosis in mouse J774 macrophages in vitro, probably by the same mechanisms that lead to osteoclast apoptosis. We have found that, in J774 macrophages, nitrogen-containing bisphosphonates (such as alendronate, ibandronate, and risedronate) inhibit post-translational modification (prenylation) of proteins, including the GTP-binding protein Ras, with farnesyl or geranylgeranyl isoprenoid groups. Clodronate did not inhibit protein prenylation. Mevastatin, an inhibitor of 3-hydroxy-3-methylglutatyl (HMG)-CoA reductase and hence the biosynthetic pathway required for the production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, also caused apoptosis in J774 macrophages and murine osteoclasts in vitro. Furthermore, alendronate-induced apoptosis, like mevastatin-induced apoptosis, could be suppressed in J774 cells by the addition of farnesyl pyrophosphate or geranylgeranyl pyrophosphate, while the effect of alendronate on osteoclast number and bone resorption in murine calvariae in vitro could be overcome by the addition of mevalonic acid. These observations suggest that nitrogen-containing bisphosphonate drugs cause apoptosis following inhibition of post-translational prenylation of proteins such as Ras. It is likely that these potent antiresorptive bisphosphonates also inhibit bone resorption by preventing protein prenylation in osteoclasts and that enzymes of the mevalonate pathway or prenyl protein transferases are the molecular targets of the nitrogen-containing bisphosphonates. Furthermore, the data support the view that clodronate acts by a different mechanism.

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