title: Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice.
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.
authors.affiliation: Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles, CA 90033, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kikuiri
authors.forename: Insoo
authors.initials: I
authors.lastname: Kim
authors.forename: Takyoshi
authors.initials: T
authors.lastname: Yamaza
authors.forename: Kentaro
authors.initials: K
authors.lastname: Akiyama
authors.forename: Qunzhou
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Li
authors.forename: Chider
authors.initials: C
authors.lastname: Chen
authors.forename: WanJun
authors.initials: W
authors.lastname: Chen
authors.forename: Songlin
authors.initials: S
authors.lastname: Wang
authors.forename: Anh D
authors.initials: AD
authors.lastname: Le
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D003907:Dexamethasone / Q000009:adverse effects*; D004164:Diphosphonates / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007167:Immunotherapy; D007571:Jaw Diseases / Q000139:chemically induced* / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010020:Osteonecrosis / Q000139:chemically induced* / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D016207:Cytokines; D004164:Diphosphonates; D007093:Imidazoles; D007166:Immunosuppressive Agents; D000077211:Zoledronic Acid; D003907:Dexamethasone