Nitrogen-containing biophosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras: reprinted from JBMR, vol. 13, pg. 581-589, 1998

Steven P Luckman, David E Hughes, Fraser Coxon, Graham G Russell, Michael J. Rogers

Research output: Contribution to journalArticle

9 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 bio-synthetic 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)1265-1274
Number of pages10
JournalJournal of Bone and Mineral Research
Volume20
Issue number7
DOIs
Publication statusPublished - 1 Jul 2005

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
Terpenes
Coenzyme A
Post Translational Protein Processing
Transferases
Skull
Oxidoreductases

Keywords

  • animals
  • bone resorption
  • cultured cells
  • diphosphonates
  • GTP-binding proteins
  • 20th century history
  • lovastatin
  • mevalonic acid
  • mice
  • osteoclasts
  • protein prenylation
  • Ras proteins
  • induce apoptosis
  • growth
  • biosynthesis
  • membrane
  • in vitro
  • isoprenylation

Cite this

Nitrogen-containing biophosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras : reprinted from JBMR, vol. 13, pg. 581-589, 1998. / Luckman, Steven P; Hughes, David E; Coxon, Fraser; Russell, Graham G; Rogers, Michael J.

In: Journal of Bone and Mineral Research, Vol. 20, No. 7, 01.07.2005, p. 1265-1274.

Research output: Contribution to journalArticle

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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 bio-synthetic 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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