Departmental Papers (Dental)

Document Type

Journal Article

Date of this Version

6-15-2013

Publication Source

Clinical Cancer Research

Volume

19

Issue

12

Start Page

3176

Last Page

3188

DOI

10.1158/1078-0432.CCR-13-0042

Abstract

Purpose

Osteonecrosis of the jaw (ONJ) is emerging as one of the important complications in cancer patients treated with antiresorptive agents. This study explored the potential role of IL-17-mediated M1/M2 macrophage alterations in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ).

Experimental Design

The expression of IL-17 and M1 and M2 macrophage markers at the local mucosal site of human BRONJ lesions was examined by immunofluorescence studies. BRONJ-like disease was induced in C57BL/6 mice and multiple myeloma (MM)-burdened mice by intravenous injection of zoledronate to evaluate the correlation of elevated IL-17 levels with changes in M1 and M2 macrophage phenotypes and the therapeutic effects of blocking IL-17 on pathogenesis of BRONJ-like disease.

Results

Increased Th17 cells and IL-17 cytokine correlate with an increase in M1/M2 macrophages ratio at the local mucosal site of both murine and human BRONJ lesion. Convincingly, in mice burdened with multiple myeloma, a combination of elevated suprabasal level and drug-induced IL-17 activity augmented the incidence of BRONJ; both systemic increase of IL-17 and disease severity could be reversed by adoptive transfer of ex vivo expanded M2 macrophages. Targeting IL-17 via specific neutralizing antibodies or a small inhibitory molecule, Laquinimod, significantly decreased M1/M2 ratio and concomitantly suppressed BRONJ-like condition in mice. Mechanistically, IL-17 enhanced IFN-γ-induced M1 polarization through augmenting STAT-1 phosphorylation while suppressed IL-4-mediated M2 conversion via inhibiting STAT-6 activation.

Conclusions

These findings have established a compelling linkage between activated IL-17-mediated polarization of M1 macrophages and the development of BRONJ-like conditions in both human disease and murine models.

Copyright/Permission Statement

Zhang, Q., Atsuta, I., Liu, S., Chen, C., Shi, S., Shi, S., & Le, A. D. (2013). IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 19(12), 3176-3188. doi: 10.1158/1078-0432.CCR-13-0042

Comments

At the time of publication, author Songtao Shi was affiliated with the University of Southern California, Los Angeles. Currently, he is a faculty member at the Dental School at the University of Pennsylvania.

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Date Posted: 01 March 2022

This document has been peer reviewed.