Research Papers: Immunology:

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

Han-Ching Tseng _, Keiichi Kanayama, Kawaljit Kaur, So-Hyun Park, Sil Park, Anna Kozlowska, Shuting Sun, Charles E. McKenna, Ichiro Nishimura and Anahid Jewett

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Oncotarget. 2015; 6:20002-20025. https://doi.org/10.18632/oncotarget.4755

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Han-Ching Tseng1,*, Keiichi Kanayama2,3,*, Kawaljit Kaur1,*, So-Hyun Park1, Sil Park1,2, Anna Kozlowska1,4, Shuting Sun5, Charles E. McKenna5, Ichiro Nishimura1,2, Anahid Jewett1

1Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA

2Division of Advanced Prosthodontics, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, USA

3Department of Periodontology, Asahi University School of Dentistry, Gifu, Japan

4Department of Tumor Immunology, Poznan University of Medical Sciences Poznan, Poland

5Department of Chemistry, University of Southern California, Los Angeles, CA, USA

*These authors have contributed equally to this work

Correspondence to:

Corresponding author: Anahid Jewett, email: [email protected]

Co-corresponding author: Ichiro Nishimura, email: [email protected]

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

Received: May 22, 2015     Accepted: July 03, 2015     Published: July 28, 2015


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-α 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.

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