Statins prevent bisphosphonate-induced ¿d-T-cell proliferation and activation in vitro

Keith Thompson, Michael John Rogers

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

Introduction: The acute phase response is the major adverse effect of intravenously administered nitrogen-containing bisphosphonate drugs (N-BPs), used in the treatment of metabolic bone diseases. This effect has recently been attributed to their action as non-peptide antigens and direct stimulation of gamma,delta-T-cells. However, because N-BPs are potent inhibitors of farnesyl diphosphate (FPP) synthase, they could cause indirect activation of gamma,delta-T-cells owing to the accumulation of intermediates upstream of FPP synthase in the mevalonate pathway, such as isopentenyl diphosphate/dimethylallyl diphosphate, which are known gamma,delta-T-cell agonists.

Materials and Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and treated with N-BP, statin, or intermediates/inhibitors of the mevalonate pathway for 7 days in the presence of interleukin (IL)-2. Flow cytometric analysis of the T-cell-gated population was used to quantify the proportion of gamma,delta-T-cells in the CD3(+) population.

Results and Conclusions: The ability of N-BPs to stimulate proliferation of CD3(+) gamma,delta-T-cells in human PBMC cultures matched the ability to inhibit FPP synthase. gamma,delta-T-cell proliferation and activation (interferon gamma [IFNgamma] and TNFalpha release) was prevented by mevastatin or lovastatin, which inhibit HMG-CoA reductase upstream of FPP synthase and prevent the synthesis of isopentenyl diphosphate/dimethylallyl diphosphate. Desoxolovastatin, an analog of lovastatin incapable of inhibiting HMG-CoA reductase, did not overcome the stimulatory effect of N-BP. Furthermore, statins did not prevent the activation of gamma,delta-T-cells by a synthetic gamma,delta-T-cell agonist or by anti-CD3 antibody. Together, these observations show that N-BPs indirectly stimulate the proliferation and activation of gamma,delta-T-cells caused by inhibition of FPP synthase and intracellular accumulation of isopentenyl diphosphate/ dimethylallyl diphosphate in PBMCs. Because activation of gamma,delta-T-cells could be the initiating event in the acute phase response to bisphosphonate therapy, co-administration of a statin could be an effective approach to prevent this adverse effect.

Original languageEnglish
Pages (from-to)278-288
Number of pages11
JournalJournal of Bone and Mineral Research
Volume19
Issue number2
Early online date16 Dec 2003
DOIs
Publication statusPublished - Feb 2004

Keywords

  • acute phase response
  • farnesyl diphosphate synthase
  • osteoporosis
  • mevalonate
  • osteoclast
  • DELTA-T-cells
  • nitrogen-containing bisphosphonates
  • acute-phase response
  • pagets-disease
  • nonpeptide antigens
  • postmenopausal osteoperosis
  • bone metastases
  • zoledronic acid
  • tumor-cells

Cite this

Statins prevent bisphosphonate-induced ¿d-T-cell proliferation and activation in vitro. / Thompson, Keith; Rogers, Michael John.

In: Journal of Bone and Mineral Research, Vol. 19, No. 2, 02.2004, p. 278-288.

Research output: Contribution to journalArticle

Thompson, Keith ; Rogers, Michael John. / Statins prevent bisphosphonate-induced ¿d-T-cell proliferation and activation in vitro. In: Journal of Bone and Mineral Research. 2004 ; Vol. 19, No. 2. pp. 278-288.
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T1 - Statins prevent bisphosphonate-induced ¿d-T-cell proliferation and activation in vitro

AU - Thompson, Keith

AU - Rogers, Michael John

PY - 2004/2

Y1 - 2004/2

N2 - Introduction: The acute phase response is the major adverse effect of intravenously administered nitrogen-containing bisphosphonate drugs (N-BPs), used in the treatment of metabolic bone diseases. This effect has recently been attributed to their action as non-peptide antigens and direct stimulation of gamma,delta-T-cells. However, because N-BPs are potent inhibitors of farnesyl diphosphate (FPP) synthase, they could cause indirect activation of gamma,delta-T-cells owing to the accumulation of intermediates upstream of FPP synthase in the mevalonate pathway, such as isopentenyl diphosphate/dimethylallyl diphosphate, which are known gamma,delta-T-cell agonists.Materials and Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and treated with N-BP, statin, or intermediates/inhibitors of the mevalonate pathway for 7 days in the presence of interleukin (IL)-2. Flow cytometric analysis of the T-cell-gated population was used to quantify the proportion of gamma,delta-T-cells in the CD3(+) population.Results and Conclusions: The ability of N-BPs to stimulate proliferation of CD3(+) gamma,delta-T-cells in human PBMC cultures matched the ability to inhibit FPP synthase. gamma,delta-T-cell proliferation and activation (interferon gamma [IFNgamma] and TNFalpha release) was prevented by mevastatin or lovastatin, which inhibit HMG-CoA reductase upstream of FPP synthase and prevent the synthesis of isopentenyl diphosphate/dimethylallyl diphosphate. Desoxolovastatin, an analog of lovastatin incapable of inhibiting HMG-CoA reductase, did not overcome the stimulatory effect of N-BP. Furthermore, statins did not prevent the activation of gamma,delta-T-cells by a synthetic gamma,delta-T-cell agonist or by anti-CD3 antibody. Together, these observations show that N-BPs indirectly stimulate the proliferation and activation of gamma,delta-T-cells caused by inhibition of FPP synthase and intracellular accumulation of isopentenyl diphosphate/ dimethylallyl diphosphate in PBMCs. Because activation of gamma,delta-T-cells could be the initiating event in the acute phase response to bisphosphonate therapy, co-administration of a statin could be an effective approach to prevent this adverse effect.

AB - Introduction: The acute phase response is the major adverse effect of intravenously administered nitrogen-containing bisphosphonate drugs (N-BPs), used in the treatment of metabolic bone diseases. This effect has recently been attributed to their action as non-peptide antigens and direct stimulation of gamma,delta-T-cells. However, because N-BPs are potent inhibitors of farnesyl diphosphate (FPP) synthase, they could cause indirect activation of gamma,delta-T-cells owing to the accumulation of intermediates upstream of FPP synthase in the mevalonate pathway, such as isopentenyl diphosphate/dimethylallyl diphosphate, which are known gamma,delta-T-cell agonists.Materials and Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and treated with N-BP, statin, or intermediates/inhibitors of the mevalonate pathway for 7 days in the presence of interleukin (IL)-2. Flow cytometric analysis of the T-cell-gated population was used to quantify the proportion of gamma,delta-T-cells in the CD3(+) population.Results and Conclusions: The ability of N-BPs to stimulate proliferation of CD3(+) gamma,delta-T-cells in human PBMC cultures matched the ability to inhibit FPP synthase. gamma,delta-T-cell proliferation and activation (interferon gamma [IFNgamma] and TNFalpha release) was prevented by mevastatin or lovastatin, which inhibit HMG-CoA reductase upstream of FPP synthase and prevent the synthesis of isopentenyl diphosphate/dimethylallyl diphosphate. Desoxolovastatin, an analog of lovastatin incapable of inhibiting HMG-CoA reductase, did not overcome the stimulatory effect of N-BP. Furthermore, statins did not prevent the activation of gamma,delta-T-cells by a synthetic gamma,delta-T-cell agonist or by anti-CD3 antibody. Together, these observations show that N-BPs indirectly stimulate the proliferation and activation of gamma,delta-T-cells caused by inhibition of FPP synthase and intracellular accumulation of isopentenyl diphosphate/ dimethylallyl diphosphate in PBMCs. Because activation of gamma,delta-T-cells could be the initiating event in the acute phase response to bisphosphonate therapy, co-administration of a statin could be an effective approach to prevent this adverse effect.

KW - acute phase response

KW - farnesyl diphosphate synthase

KW - osteoporosis

KW - mevalonate

KW - osteoclast

KW - DELTA-T-cells

KW - nitrogen-containing bisphosphonates

KW - acute-phase response

KW - pagets-disease

KW - nonpeptide antigens

KW - postmenopausal osteoperosis

KW - bone metastases

KW - zoledronic acid

KW - tumor-cells

U2 - 10.1359/JBMR.0301230

DO - 10.1359/JBMR.0301230

M3 - Article

VL - 19

SP - 278

EP - 288

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 2

ER -