Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw–like Disease in Mice

Patients on high-dose bisphosphonate and immunosuppressive therapy have an increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ); despite the disease severity, its pathophysiology remains unknown, and appropriate therapy is not established. Here we have developed a mouse model of...

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Main Authors:	Kikuiri, Takashi, Kim, Insoo, Yamaza, Takyoshi, Akiyama, Kentaro, Zhang, Qunzhou, Li, Yunsheng, Chen, Chider, Chen, WanJun, Wang, Songlin, Le, Anh D, Shi, Songtao
Format:	Online
Language:	English
Published:	Wiley Subscription Services, Inc., A Wiley Company 2010
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154005/

id	pubmed-3154005
recordtype	oai_dc
spelling	pubmed-31540052011-08-19 Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw–like Disease in Mice Kikuiri, Takashi Kim, Insoo Yamaza, Takyoshi Akiyama, Kentaro Zhang, Qunzhou Li, Yunsheng Chen, Chider Chen, WanJun Wang, Songlin Le, Anh D Shi, Songtao Original Article Patients on high-dose bisphosphonate and immunosuppressive therapy have an increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ); despite the disease severity, its pathophysiology remains unknown, and appropriate therapy is not established. Here we have developed a mouse model of BRONJ-like disease that recapitulates major clinical and radiographic manifestations of the human disease, including characteristic features of an open alveolar socket, exposed necrotic bone or sequestra, increased inflammatory infiltrates, osseous sclerosis, and radiopaque alveolar bone. We show that administration of zoledronate, a potent aminobisphosphonate, and dexamethasone, an immunosuppressant drug, causes BRONJ-like disease in mice in part by suppressing the adaptive regulatory T cells, Tregs, and activating the inflammatory T-helper-producing interleukin 17 cells, Th17. Most interestingly, we demonstrate that systemic infusion with mesenchymal stem cells (MSCs) prevents and cures BRONJ-like disease possibly via induction of peripheral tolerance, shown as an inhibition of Th17 and increase in Treg cells. The suppressed Tregs/Th17 ratio in zoledronate- and dexamethasone-treated mice is restored in mice undergoing salvage therapy with Tregs. These findings provide evidence of an immunity-based mechanism of BRONJ-like disease and support the rationale for in vivo immunomodulatory therapy using Tregs or MSCs to treat BRONJ. © 2010 American Society for Bone and Mineral Research. Wiley Subscription Services, Inc., A Wiley Company 2010-07 2010-01-29 /pmc/articles/PMC3154005/ /pubmed/20200952 http://dx.doi.org/10.1002/jbmr.37 Text en Copyright © 2010 American Society for Bone and Mineral Research http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kikuiri, Takashi Kim, Insoo Yamaza, Takyoshi Akiyama, Kentaro Zhang, Qunzhou Li, Yunsheng Chen, Chider Chen, WanJun Wang, Songlin Le, Anh D Shi, Songtao
spellingShingle	Kikuiri, Takashi Kim, Insoo Yamaza, Takyoshi Akiyama, Kentaro Zhang, Qunzhou Li, Yunsheng Chen, Chider Chen, WanJun Wang, Songlin Le, Anh D Shi, Songtao Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw–like Disease in Mice
author_facet	Kikuiri, Takashi Kim, Insoo Yamaza, Takyoshi Akiyama, Kentaro Zhang, Qunzhou Li, Yunsheng Chen, Chider Chen, WanJun Wang, Songlin Le, Anh D Shi, Songtao
author_sort	Kikuiri, Takashi
title	Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw–like Disease in Mice
title_short	Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw–like Disease in Mice
title_full	Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw–like Disease in Mice
title_fullStr	Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw–like Disease in Mice
title_full_unstemmed	Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw–like Disease in Mice
title_sort	cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw–like disease in mice
description	Patients on high-dose bisphosphonate and immunosuppressive therapy have an increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ); despite the disease severity, its pathophysiology remains unknown, and appropriate therapy is not established. Here we have developed a mouse model of BRONJ-like disease that recapitulates major clinical and radiographic manifestations of the human disease, including characteristic features of an open alveolar socket, exposed necrotic bone or sequestra, increased inflammatory infiltrates, osseous sclerosis, and radiopaque alveolar bone. We show that administration of zoledronate, a potent aminobisphosphonate, and dexamethasone, an immunosuppressant drug, causes BRONJ-like disease in mice in part by suppressing the adaptive regulatory T cells, Tregs, and activating the inflammatory T-helper-producing interleukin 17 cells, Th17. Most interestingly, we demonstrate that systemic infusion with mesenchymal stem cells (MSCs) prevents and cures BRONJ-like disease possibly via induction of peripheral tolerance, shown as an inhibition of Th17 and increase in Treg cells. The suppressed Tregs/Th17 ratio in zoledronate- and dexamethasone-treated mice is restored in mice undergoing salvage therapy with Tregs. These findings provide evidence of an immunity-based mechanism of BRONJ-like disease and support the rationale for in vivo immunomodulatory therapy using Tregs or MSCs to treat BRONJ. © 2010 American Society for Bone and Mineral Research.
publisher	Wiley Subscription Services, Inc., A Wiley Company
publishDate	2010
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154005/
_version_	1611470339321102336

Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw–like Disease in Mice

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