Departmental Papers (Dental)
Document Type
Journal Article
Date of this Version
7-2010
Publication Source
Journal of Bone and Mineral Research
Volume
25
Issue
7
Start Page
1668
Last Page
1679
DOI
10.1002/jbmr.37
Abstract
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.
Keywords
Author keywords: Bisphosphonate, Interleukin 17, Mesenchymal stem cell, Osteonecrosis, Th17, Treg MeSH: Animals, Cytokines, Dexamethasone, Diphosphonates, Disease Models, Animal, Female, Imidazoles, Immunosuppressive Agents, Immunotherapy, Jaw Diseases, Mesenchymal Stem Cell Transplantation, Mice, Mice, Inbred C57BL, Mice, Nude, Osteonecrosis, T-Lymphocytes, Regulatory EMTREE drug terms: dexamethasone, zoledronic acid EMTREE medical terms: alveolar bone, animal experiment, animal model, animal tissue, article, controlled study, female, immunomodulation, immunotherapy, inflammatory infiltrate, jaw osteonecrosis, mesenchymal stem cell transplantation, mouse, nonhuman, regulatory T lymphocyte, Th17 cell
Recommended Citation
Kikuiri, T., Kim, I., Yamaza, T., Akiyama, K., Zhang, Q., Li, Y., Chen, C., Chen, W., Wang, S., Le, A. D., & Shi, S. (2010). Cell-based Immunotherapy with Mesenchymal Stem Cells Cures Bisphosphonate-related Osteonecrosis of the Jaw-like Disease in Mice. Journal of Bone and Mineral Research, 25 (7), 1668-1679. http://dx.doi.org/10.1002/jbmr.37
Included in
Endodontics and Endodontology Commons, Oral and Maxillofacial Surgery Commons, Oral Biology and Oral Pathology Commons, Periodontics and Periodontology Commons
Date Posted: 10 February 2023
This document has been peer reviewed.
Comments
At the time of publication, author Qunzhou Zhang was affiliated with the University of Southern California School of Dentistry]. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.
At the time of publication, author Chider Chen was affiliated with the University of Southern California School of Dentistry]. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.
At the time of publication, author Anh D. Le was affiliated with the University of Southern California School of Dentistry]. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.
At the time of publication, author Songtao Shi was affiliated with the University of Southern California School of Dentistry]. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.