Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice

Takashi Kikuiri, Insoo Kim, Takyoshi Yamaza, Kentaro Akiyama, Qunzhou Zhang, Yunsheng Li, Chider Chen, WanJun Chen, Songlin Wang, Anh D. Le, Songtao Shi

Research output: Contribution to journalArticle

114 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1668-1679
Number of pages12
JournalJournal of Bone and Mineral Research
Volume25
Issue number7
DOIs
Publication statusPublished - Jul 2010
Externally publishedYes

Fingerprint

Jaw Diseases
Bisphosphonate-Associated Osteonecrosis of the Jaw
Mesenchymal Stromal Cells
Immunotherapy
zoledronic acid
Regulatory T-Lymphocytes
Immunosuppressive Agents
Dexamethasone
Peripheral Tolerance
Th17 Cells
Bone and Bones
Salvage Therapy
Immunomodulation
Interleukin-17
Diphosphonates
Sclerosis
Immunity
Therapeutics

Keywords

  • Bisphosphonate
  • Interleukin 17
  • Mesenchymal stem cell
  • Osteonecrosis
  • Th17
  • Treg

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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.

In: Journal of Bone and Mineral Research, Vol. 25, No. 7, 07.2010, p. 1668-1679.

Research output: Contribution to journalArticle

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. In: Journal of Bone and Mineral Research. 2010 ; Vol. 25, No. 7. pp. 1668-1679.
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