Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation

evidence from structure-activity relationships in J774 macrophages

S P Luckman, Fraser Coxon, F H Ebetino, R Graham G Russell, Michael John Rogers

Research output: Contribution to journalArticle

220 Citations (Scopus)

Abstract

Recent evidence suggests that bisphosphonates (BPs) may inhibit bone resorption by mechanisms that lead to osteoclast apoptosis. We have previously shown that BPs also reduce cell viability and induce apoptosis in the macrophage-like cell line J774. To determine whether BPs inhibit osteoclast-mediated bone resorption and affect J774 macrophages by the same molecular mechanism, we examined the potency to reduce J774 cell viability of pairs of nitrogen-containing BPs that differ slightly in the structure of the heterocycle-containing side chain but that differ markedly in antiresorptive potency. In all cases, the most potent antiresorptive BP of each pair also caused the greatest loss of J774 viability, while the less potent antiresorptive BPs were also less potent at reducing J774 cell viability. Similarly, the bisphosphinate, phosphonoalkylphosphinate and monophosphonate analogs of BPs (in which one or both phosphonate groups are modified, giving rise to much less potent or inactive antiresorptive agents) were much less potent or inactive at reducing J774 cell viability. Thus, the structure-activity relationships of BPs for inhibiting bone resorption match those for causing loss of cell viability in J774 cells, indicating that BPs inhibit osteoclast-mediated bone resorption and reduce J774 macrophage viability by the same molecular mechanism. Loss of J774 cell viability after treatment with BPs was associated with a parallel increase in apoptotic cell death. We have recently proposed that nitrogen-containing BPs reduce cell viability and cause J774 apoptosis as a consequence of inhibition of enzymes of the mevalonate pathway and hence loss of prenylated proteins. In this study, the BPs that were potent inducers of J774 apoptosis and potent antiresorptive agents were also found to be effective inhibitors of protein prenylation in J774 macrophages, whereas the less potent BP analogs did not inhibit protein prenylation. This provides strong evidence that BPs with a heterocyclic, nitrogen-containing side chain, such as risedronate, inhibit osteoclast-mediated bone resorption and induce J774 apoptosis by preventing protein prenylation.
Original languageEnglish
Pages (from-to)1668-1678
Number of pages11
JournalJournal of Bone and Mineral Research
Volume13
Issue number11
DOIs
Publication statusPublished - 1 Nov 1998

Fingerprint

Protein Prenylation
Diphosphonates
Structure-Activity Relationship
Bone Resorption
Macrophages
Apoptosis
Cell Survival
Osteoclasts
Bone Density Conservation Agents
Nitrogen
Organophosphonates
Mevalonic Acid

Keywords

  • Animals
  • Apoptosis
  • Bone Resorption
  • Cell Nucleus
  • Cells, Cultured
  • DNA
  • DNA Fragmentation
  • Diphosphonates
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Macrophages
  • Mice
  • Microscopy, Fluorescence
  • Protein Prenylation
  • Structure-Activity Relationship

Cite this

Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation : evidence from structure-activity relationships in J774 macrophages. / Luckman, S P; Coxon, Fraser; Ebetino, F H; Russell, R Graham G; Rogers, Michael John.

In: Journal of Bone and Mineral Research, Vol. 13, No. 11, 01.11.1998, p. 1668-1678.

Research output: Contribution to journalArticle

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AB - Recent evidence suggests that bisphosphonates (BPs) may inhibit bone resorption by mechanisms that lead to osteoclast apoptosis. We have previously shown that BPs also reduce cell viability and induce apoptosis in the macrophage-like cell line J774. To determine whether BPs inhibit osteoclast-mediated bone resorption and affect J774 macrophages by the same molecular mechanism, we examined the potency to reduce J774 cell viability of pairs of nitrogen-containing BPs that differ slightly in the structure of the heterocycle-containing side chain but that differ markedly in antiresorptive potency. In all cases, the most potent antiresorptive BP of each pair also caused the greatest loss of J774 viability, while the less potent antiresorptive BPs were also less potent at reducing J774 cell viability. Similarly, the bisphosphinate, phosphonoalkylphosphinate and monophosphonate analogs of BPs (in which one or both phosphonate groups are modified, giving rise to much less potent or inactive antiresorptive agents) were much less potent or inactive at reducing J774 cell viability. Thus, the structure-activity relationships of BPs for inhibiting bone resorption match those for causing loss of cell viability in J774 cells, indicating that BPs inhibit osteoclast-mediated bone resorption and reduce J774 macrophage viability by the same molecular mechanism. Loss of J774 cell viability after treatment with BPs was associated with a parallel increase in apoptotic cell death. We have recently proposed that nitrogen-containing BPs reduce cell viability and cause J774 apoptosis as a consequence of inhibition of enzymes of the mevalonate pathway and hence loss of prenylated proteins. In this study, the BPs that were potent inducers of J774 apoptosis and potent antiresorptive agents were also found to be effective inhibitors of protein prenylation in J774 macrophages, whereas the less potent BP analogs did not inhibit protein prenylation. This provides strong evidence that BPs with a heterocyclic, nitrogen-containing side chain, such as risedronate, inhibit osteoclast-mediated bone resorption and induce J774 apoptosis by preventing protein prenylation.

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KW - Dose-Response Relationship, Drug

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KW - Mice

KW - Microscopy, Fluorescence

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