Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: role in osteoclast-mediated NK cell activation

Oncotarget. 2015 Aug 21;6(24):20002-25. doi: 10.18632/oncotarget.4755.


The aim of this study is to establish osteoclasts as key immune effectors capable of activating the function of Natural Killer (NK) cells, and expanding their numbers, and to determine in vivo and in vitro effect of bisphosphonates (BPs) during NK cell interaction with osteoclasts and on systemic and local immune function. The profiles of 27 cytokines, chemokines and growth factors released from osteoclasts were found to be different from dendritic cells and M1 macrophages but resembling to untreated monocytes and M2 macrophages. Nitrogen-containing BPs Zoledronate (ZOL) and Alendronate (ALN), but not non-nitrogen-containing BPs Etidronate (ETI), triggered increased release of pro-inflammatory mediators from osteoclasts while all three BPs decreased pit formation by osteoclasts. ZOL and ALN mediated significant release of IL-6, TNF-` and IL-1β, whereas they inhibited IL-10 secretion by osteoclasts. Treatment of osteoclasts with ZOL inhibited NK cell mediated cytotoxicity whereas it induced significant secretion of cytokines and chemokines. NK cells lysed osteoclasts much more than their precursor cells monocytes, and this correlated with the decreased expression of MHC class I expression on osteoclasts. Intravenous injection of ZOL in mice induced pro-inflammatory microenvironment in bone marrow and demonstrated significant immune activation. By contrast, tooth extraction wound of gingival tissues exhibited profound immune suppressive microenvironment associated with dysregulated wound healing to the effect of ZOL which could potentially be responsible for the pathogenesis of Osteonecrosis of the Jaw (ONJ). Finally, based on the data obtained in this paper we demonstrate that osteoclasts can be used as targets for the expansion of NK cells with superior function for immunotherapy of cancer.

Keywords: Immune response; Immunity; Immunology and Microbiology Section; NK cell; bisphosphonate; etidronate; osteoclasts; zoledronate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alendronate / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Bone Marrow / drug effects*
  • Bone Marrow / immunology
  • Cell Communication / drug effects
  • Cell Communication / immunology
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Diphosphonates / pharmacology*
  • Female
  • Gingiva / drug effects*
  • Gingiva / immunology
  • Humans
  • Imidazoles / pharmacology
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / drug effects
  • Monocytes / immunology
  • Osteoclasts / drug effects*
  • Osteoclasts / immunology
  • Zoledronic Acid


  • Diphosphonates
  • Imidazoles
  • Zoledronic Acid
  • Alendronate