The Role of Geranylgeranylation in Bone Resorption and Its Suppression by Bisphosphonates in Fetal Bone Explants In Vitro: A Clue to the Mechanism of Action of Nitrogen‐Containing Bisphosphonates

@article{vanBeek1999TheRO,
  title={The Role of Geranylgeranylation in Bone Resorption and Its Suppression by Bisphosphonates in Fetal Bone Explants In Vitro: A Clue to the Mechanism of Action of Nitrogen‐Containing Bisphosphonates},
  author={Ermond R. van Beek and C W L{\"o}wik and Gabri van der Pluijm and Socrates E Papapoulos},
  journal={Journal of Bone and Mineral Research},
  year={1999},
  volume={14}
}
Bisphosphonates, synthetic compounds used in the treatment of skeletal disorders, suppress osteoclast‐mediated bone resorption by a yet unidentified mechanism. Previous studies showed that some bisphosphonates can inhibit enzymes of the mevalonate pathway, and nitrogen‐containing bisphosphonates inhibit protein prenylation in mouse macrophages. In the present study, we examined the involvement of the mevalonate pathway in basal and bisphosphonate‐inhibited osteoclastic resorption in fetal mouse… Expand
Protein Geranylgeranylation Is Required for Osteoclast Formation, Function, and Survival: Inhibition by Bisphosphonates and GGTI‐298
  • F. Coxon, M. Helfrich, +4 authors M. Rogers
  • Biology, Medicine
  • Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
  • 2000
TLDR
The results therefore show the molecular mechanism of action of nitrogen‐containing bisphosphonate drugs in osteoclasts and highlight the fundamental importance of geranylgeranylated proteins in osteoclast formation and function. Expand
Bisphosphonates suppress bone resorption by a direct effect on early osteoclast precursors without affecting the osteoclastogenic capacity of osteogenic cells: the role of protein geranylgeranylation in the action of nitrogen-containing bisphosphonates on osteoclast precursors.
TLDR
Results indicate that Bps can suppress osteoclastic resorption in vitro by a direct action on very early osteoclast precursors at the bone surface, and not by affecting the osteooclastogenic capacity of osteogenic cells. Expand
Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis.
TLDR
It is found that alendronate and risedronate inhibit bone resorption (in pit assays) at doses tenfold lower than those reducing osteoclast number, which indicates that, whereas induction of apoptosis plays a major role in etidronsate and clodronate inhibition of resOrption, alendronsates and risingronate suppression of bone res orption is independent of their effects on apoptosis. Expand
Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates.
TLDR
The potency of a wider range of nitrogen-containing bisphosphonates, including the highly potent, heterocycle-containing zoledronic acid and minodronate, is examined, finding a clear correlation between the ability to inhibit farnesyl diphosphate synthase in vitro, and to inhibit protein prenylation in cell-free extracts and in purified osteoclasts in vitro and in vivo. Expand
A novel inhibitory mechanism of nitrogen-containing bisphosphonate on the activity of Cl− extrusion in osteoclasts
TLDR
It is suggested that nitrogen-containing bisphosphonates suppress the activity of osteoclastic acid-activated Cl− currents through FDPS inhibition, suggesting the inhibition of Cl− extrusion activity. Expand
Independent pathways in the modulation of osteoclastic resorption by intermediates of the mevalonate biosynthetic pathway: the role of the retinoic acid receptor.
TLDR
Both GGOH and GGPP, independent of protein prenylation, stimulate osteoclastic bone resorption via RAR, probably via metabolism into GGA, which indicates the functional involvement of the RAR in the action of these polyisoprenoids. Expand
Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates.
TLDR
Alkyl and heterocyclic NBPS suppressed bone resorption and FPPS/IPPI activity, and the antiresorptive effect of pamidronate was only partially reversible with GGOH, indicating the involvement of mechanism(s) of action additional to that of suppression of FPPS. Expand
Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity.
TLDR
The studies suggest that the effects of nitrogen-containing bisphosphonates observed in the GI tract may be due to inhibition of proliferation or apoptosis of gut epithelial cells, following loss of prenylated proteins and sterols. Expand
Biochemical and molecular mechanisms of action of bisphosphonates.
TLDR
These discoveries are also giving insights into some of the adverse effects of bisphosphonates, such as the acute phase reaction that is triggered by inhibition of FPP synthase in peripheral blood monocytes. Expand
The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis.
TLDR
These results provide the first direct evidence that the antiinflammatory and antiresorptive effects of clodronate on macrophages and osteoclasts in vivo occur via the intracellular formation of AppCCl2p. Expand
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