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

Keith Thompson, Michael John Rogers

Research output: Contribution to journalArticle

183 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