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

Beek, Ermond van; Löwik, Clemens W.G.M.; Pluijm, Gabri van der; Papapoulos, Socrates E.

doi:10.1359/jbmr.1999.14.5.722

Cited by 220 publications

(115 citation statements)

References 28 publications

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“…These analogues of FPP and GGPP have been reported to display greater membrane permeability and be converted to the respective pyrophosphate forms intracellularly by a salvage pathway (Crick et al, 1997). In osteoclasts, N-BP-induced apoptosis was attenuated by addition of GGOH but not FOH (Fisher et al, 1999;van Beek et al, 1999b). However, in J774 macrophages undergoing N-BP induced apoptosis, addition of either FOH or GGOH (Benford et al, 1999) inhibited caspase-3 activation and induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Mansi

2002

Br J Cancer

128

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Bisphosphonates are well established in the management of cancer-induced bone disease. Recent studies have indicated that these compounds have direct inhibitory effects on cultured human breast cancer cells. Nitrogen-containing bisphosphonates including zoledronic acid have been shown to induce apoptosis associated with PARP cleavage and DNA fragmentation. The aim of this study was to identify the signalling pathways involved. Forced expression of the anti-apoptotic protein bcl-2 attenuated bisphosphonate-induced loss of cell viability and induction of DNA fragmentation in MDA-MB-231 cells. Zoledronic acid-mediated apoptosis was associated with a time and dose-related release of mitochondrial cytochrome c into the cytosol in two cell lines. Rescue of cells by preincubation with a caspase-3 selective inhibitor and demonstration of procaspase-3 cleavage products by immunoblotting suggests that at least one of the caspases activated in response to zoledronic acid treatment is caspase-3. In both MDA-MB-231 and MCF-7 breast cancer cells, zoledronic acid impaired membrane localisation of Ras indicating reduced prenylation of this protein. These observations demonstrate that zoledronic acidmediated apoptosis is associated with cytochrome c release and consequent caspase activation. This process may be initiated by inhibition of the enzymes in the mevalonate pathway leading to impaired prenylation of key intracellular proteins including Ras.

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Section: Discussionmentioning

confidence: 99%

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Mansi

2002

Br J Cancer

128

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“…This is in agreement with previous studies demonstrating that the effects of N-BPs on osteoclasts and myeloma cells could be blocked by restoring geranylgeranylation via the addition of GGOH. 6,24,40 Coincubation with MVA, an intermediate of the mevalonate pathway FIGURE 4 -RIS dose-dependently inhibits DNA replication during S-phase in JJN-3 cells. JJN-3 human myeloma cells were treated with vehicle only, 1, 10 or 100 lM RIS, or 3 mM 3-PEHPC for 48 hr.…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S‐phase arrest, in human myeloma cells

Roelofs¹,

Hulley²,

Meijer³

et al. 2006

Intl Journal of Cancer

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Bisphosphonates (BPs) are widely used in the treatment of osteolytic bone disease associated with multiple myeloma, and have been demonstrated to exert antitumor effects both in vitro and in vivo. However, the precise molecular mechanisms involved in the direct antitumor effects of BPs in vitro are not known. Nitrogen‐containing BPs, such as risedronate (RIS), act by inhibiting protein prenylation. A phosphonocarboxylate analogue of RIS, 3‐PEHPC, has previously been shown in osteoclasts and macrophages to specifically inhibit prenylation of Rab GTPases. The aim of this study was to identify the molecular targets of RIS and 3‐PEHPC in human myeloma cells and to determine the cellular effects of selective inhibition of Rab prenylation by 3‐PEHPC as compared to nonspecific inhibition of protein prenylation by RIS in human myeloma cells. RIS dose‐dependently inhibited prenylation of both Rap1A and Rab6, whereas 3‐PEHPC only inhibited Rab6 prenylation. Both RIS and 3‐PEHPC dose‐dependently increased apoptosis in human myeloma cells. RIS induced an accumulation of cells in the S‐phase of the cell cycle, associated with inhibition of DNA replication. In contrast, 3‐PEHPC did not cause cell‐cycle arrest. Furthermore, geranylgeraniol could prevent inhibition of prenylation, induction of apoptosis, and cell‐cycle arrest in response to RIS, but not inhibition of Rab prenylation and apoptosis induced by 3‐PEHPC, consistent with specific inhibition of Rab geranylgeranyl transferase by 3‐PEHPC. In conclusion, our studies demonstrate that selective inhibition of Rab prenylation induces apoptosis, but not S‐phase arrest, thus identifying distinct molecular pathways that mediate the antimyeloma effect of nitrogen‐containing BPs. © 2006 Wiley‐Liss, Inc.

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“…They act by promoting osteoclast apoptosis and inhibiting differentiation to mature osteoclasts [16,25,30,32,40,41] or by reducing osteoclast activity [2,10,11,15,31,38,40,44], either through an inhibition of farnesyl diphosphonate synthase (FPP) in the mevalonate pathway, or by otherwise inhibiting prenylation of small GTPases. The influence of bisphosphonates on bone formation is unknown, although it has been hypothesized, based primarily on studies in culture, that bisphosphonates inhibit osteoblast apoptosis [1,35,38] and may stimulate osteoblast proliferation and differentiation [18,19,23,26,41,42], leading to increased bone formation.…”

Section: Introductionmentioning

confidence: 99%

Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia

Iwata

Follet

et al. 2006

Bone

102

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Recent studies demonstrate that bisphosphonates suppress bone resorption by leading to apoptosis of the osteoclast and inhibiting the differentiation to mature osteoclasts. The influence of bisphosphonates on bone formation is unknown, although it has been hypothesized that bisphosphonates inhibit osteoblast apoptosis and stimulate osteoblast proliferation and differentiation in vitro, leading to increased bone formation. The purpose of this study was to investigate the effect of bisphosphonates on bone formation. We administered risedronate at 0.05, 0.5 or 5.0 μg/kg/day or alendronate at 0.1, 1.0 or 10 μg/kg/day subcutaneously for 17 days to 6-month-old female Sprague-Dawley rats. Control rats were given a daily subcutaneous injection of saline. Following sacrifice, the femoral and tibial mid-diaphyses were harvested and mineralizing surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR/BS) were measured on periosteal and endocortical surfaces. In the femur, periosteal MAR was significantly lower in all treatment groups (22-29% for risedronate, 26-36% for alendronate) than in control. In the tibia, periosteal MAR and BFR of all treatment groups were significantly lower (41-50% for risedronate, 43-52% for alendronate) than in the control group. Because the periosteal surfaces of these bones are only undergoing bone formation in modeling mode, our results show that bisphosphonates suppress bone formation independently of bone resorption. Because this effect is seen on periosteal MAR rather than on periosteal MS/BS, we hypothesize that bisphosphonates affect the activity of individual osteoblasts at the cell level. This may help to explain the reason that the anabolic effects of teriparatide are blunted when administered concurrently with or following a course of bisphosphonates in humans.

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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

Cited by 220 publications

References 28 publications

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S‐phase arrest, in human myeloma cells

Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia

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