The gunmetal mouse reveals Rab geranylgeranyl transferase to be the major molecular target of phosphonocarboxylate analogues of bisphosphonates

Fraser Coxon, Adam Taylor, Charlotte A. Stewart, Rudi Baron, Miguel C. Seabra, F. Hal Ebetino, Michael J. Rogers

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The described ability of phosphonocarboxylate analogues of bisphosphonates (BPs) to inhibit Rab geranylgeranyl transferase (RGGT) is thought to be the mechanism underlying their cellular effects, including their ability to reduce macrophage cell viability and to inhibit osteoclast-mediated resorption. However, until now the possibility that at least some of the effects of these drugs may be mediated through other targets has not been excluded. Since RGGT is the most distal enzyme in the process of Rab prenylation, it has not proved possible to confirm the mechanism underlying the effects of these drugs by adding back downstream intermediates of the mevalonate pathway, the approach used to demonstrate that bisphosphonates act through this pathway. We now confirm that RGGT is the major pharmacological target of phosphonocarboxylates by using several alternative approaches. Firstly, analysis of several different phosphonocarboxylate drugs demonstrates a very good correlation between the ability of these drugs to inhibit RGGT with their ability to: (a) reduce macrophage cell viability; (b) induce apoptosis; and (c) induce vacuolation in rabbit osteoclasts. Secondly, we have found that cells from the gunmetal (gm/gm) mouse, which bear a homozygous mutation in RGGT that results in similar to 80% reduced activity of this enzyme compared to wild-type or heterozygous mice, are more sensitive to the effects of active phosphonocarboxylates (including reducing macrophage cell viability, inhibiting osteoclast formation and inhibiting fluid-phase endocytosis), confirming that these effects are mediated through inhibition of RGGT. In conclusion, these data demonstrate that all of the pharmacological effects of phosphonocarboxylates found thus far appear to be mediated through the specific inhibition of RGGT, highlighting the potential therapeutic value of this class of drugs.

This article is part of a Special Issue entitled Bisphosphonates. (C) 2011 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)111-121
Number of pages11
JournalBone
Volume49
Issue number1
Early online date16 Mar 2011
DOIs
Publication statusPublished - Jul 2011

Keywords

  • phosphonocarboxylate
  • bisphosphonate
  • osteoclast
  • Rab prenylation
  • Rab geranylgeranyl transferase
  • nitrogen-containing bisphosphonates
  • in-vitro
  • bone-resorption
  • osteoclast formation
  • signal-transduction
  • small GTPASES
  • prenylation
  • inhibition
  • mechanism
  • proteins

Cite this

The gunmetal mouse reveals Rab geranylgeranyl transferase to be the major molecular target of phosphonocarboxylate analogues of bisphosphonates. / Coxon, Fraser; Taylor, Adam; Stewart, Charlotte A.; Baron, Rudi; Seabra, Miguel C.; Ebetino, F. Hal; Rogers, Michael J.

In: Bone, Vol. 49, No. 1, 07.2011, p. 111-121.

Research output: Contribution to journalArticle

Coxon, Fraser ; Taylor, Adam ; Stewart, Charlotte A. ; Baron, Rudi ; Seabra, Miguel C. ; Ebetino, F. Hal ; Rogers, Michael J. / The gunmetal mouse reveals Rab geranylgeranyl transferase to be the major molecular target of phosphonocarboxylate analogues of bisphosphonates. In: Bone. 2011 ; Vol. 49, No. 1. pp. 111-121.
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abstract = "The described ability of phosphonocarboxylate analogues of bisphosphonates (BPs) to inhibit Rab geranylgeranyl transferase (RGGT) is thought to be the mechanism underlying their cellular effects, including their ability to reduce macrophage cell viability and to inhibit osteoclast-mediated resorption. However, until now the possibility that at least some of the effects of these drugs may be mediated through other targets has not been excluded. Since RGGT is the most distal enzyme in the process of Rab prenylation, it has not proved possible to confirm the mechanism underlying the effects of these drugs by adding back downstream intermediates of the mevalonate pathway, the approach used to demonstrate that bisphosphonates act through this pathway. We now confirm that RGGT is the major pharmacological target of phosphonocarboxylates by using several alternative approaches. Firstly, analysis of several different phosphonocarboxylate drugs demonstrates a very good correlation between the ability of these drugs to inhibit RGGT with their ability to: (a) reduce macrophage cell viability; (b) induce apoptosis; and (c) induce vacuolation in rabbit osteoclasts. Secondly, we have found that cells from the gunmetal (gm/gm) mouse, which bear a homozygous mutation in RGGT that results in similar to 80{\%} reduced activity of this enzyme compared to wild-type or heterozygous mice, are more sensitive to the effects of active phosphonocarboxylates (including reducing macrophage cell viability, inhibiting osteoclast formation and inhibiting fluid-phase endocytosis), confirming that these effects are mediated through inhibition of RGGT. In conclusion, these data demonstrate that all of the pharmacological effects of phosphonocarboxylates found thus far appear to be mediated through the specific inhibition of RGGT, highlighting the potential therapeutic value of this class of drugs.This article is part of a Special Issue entitled Bisphosphonates. (C) 2011 Elsevier Inc. All rights reserved.",
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AU - Stewart, Charlotte A.

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AU - Seabra, Miguel C.

AU - Ebetino, F. Hal

AU - Rogers, Michael J.

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AB - The described ability of phosphonocarboxylate analogues of bisphosphonates (BPs) to inhibit Rab geranylgeranyl transferase (RGGT) is thought to be the mechanism underlying their cellular effects, including their ability to reduce macrophage cell viability and to inhibit osteoclast-mediated resorption. However, until now the possibility that at least some of the effects of these drugs may be mediated through other targets has not been excluded. Since RGGT is the most distal enzyme in the process of Rab prenylation, it has not proved possible to confirm the mechanism underlying the effects of these drugs by adding back downstream intermediates of the mevalonate pathway, the approach used to demonstrate that bisphosphonates act through this pathway. We now confirm that RGGT is the major pharmacological target of phosphonocarboxylates by using several alternative approaches. Firstly, analysis of several different phosphonocarboxylate drugs demonstrates a very good correlation between the ability of these drugs to inhibit RGGT with their ability to: (a) reduce macrophage cell viability; (b) induce apoptosis; and (c) induce vacuolation in rabbit osteoclasts. Secondly, we have found that cells from the gunmetal (gm/gm) mouse, which bear a homozygous mutation in RGGT that results in similar to 80% reduced activity of this enzyme compared to wild-type or heterozygous mice, are more sensitive to the effects of active phosphonocarboxylates (including reducing macrophage cell viability, inhibiting osteoclast formation and inhibiting fluid-phase endocytosis), confirming that these effects are mediated through inhibition of RGGT. In conclusion, these data demonstrate that all of the pharmacological effects of phosphonocarboxylates found thus far appear to be mediated through the specific inhibition of RGGT, highlighting the potential therapeutic value of this class of drugs.This article is part of a Special Issue entitled Bisphosphonates. (C) 2011 Elsevier Inc. All rights reserved.

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