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Effect of Human Umbilical Cord Matrix-Derived Mesenchymal Stem Cells on Bisphosphonate-Related Osteonecrosis of the Jaw

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe sequela caused by bisphosphonates (BPs), which are widely used to treat osteoporosis or other malignancies. However, the mechanism underlying BRONJ remains unclear. Recently, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been studied for treatment of diverse diseases and injuries. This study aimed to investigate the therapeutic effects of hUC-MSCs in BRONJ.

Methods:

The therapeutic effects of hUC-MSCs were examined in rat bone marrow (rBM)-derived cells using cell viability, colony-forming, and real-time PCR assays and FACS for analyzing essential proinflammatory and bone regeneration markers in vitro. To demonstrate the in vivo therapeutic and adverse effects of transfused hUC-MSCs, micro-CT, H&E staining, IHC (Angiogenesis marker gene expression) staining, and parathyroid hormone (PTH)/calcium assay were conducted in a BRONJ-induced animal model.

Results:

BP-induced cytotoxicity and inflammation in rBM-derived cells decreased, after co-culture with hUC-MSCs. The expression levels of bone regeneration markers (RUNX2, OSX, and BMP-2) significantly increased in BP-treated rBM-derived cells, after co-culture with hUC-MSCs. The BP-induced abnormal shift in RANKL/OPG expression ratio in rBM-derived cells was normalized by hUC-MSCs. Consistent with these in vitro results, transfused hUC-MSCs markedly decreased BRONJ and significantly healed injured mucosa in the BRONJ-induced animal model. The animals exhibited serious destruction of the kidney structure and increases in serum PTH and calcium levels, which were significantly normalized by hUC-MSC transfusion.

Conclusion:

hUC-MSCs exerted therapeutic effects on BRONJ in vitro and in vivo through their anti-cytotoxicity, anti-inflammatory activity and ability to recover bone regeneration.

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Acknowledgements

We would like to thank Asan stem cell center for providing hUC-MSCs. We also thank Professor Woo-Chan Son for the assistance with histopathologic evaluation, Asan Medical Center, for the use of their shared equipment, services, and expertise. This study was supported by a Grant (No. 2016-569) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea. This study was supported by a grant (2018-327) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

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Authors and Affiliations

  1. Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea

    Gwanghyun Yang, Young-Nam Kim, Hyunjeong Kim & Bu-Kyu Lee

  2. Department of Oral and Maxillofacial Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea

    Bu-Kyu Lee

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  1. Gwanghyun Yang
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Contributions

YNK and GY was responsible for the analysis and interpretation of the data, as well as drafting of the article. HK contributed to the study performance. BKL is the corresponding author, responsible for conception and design, as well as critical revision of the article.

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Correspondence to Bu-Kyu Lee.

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The authors have no financial conflicts of interest.

Ethical statement

This study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) Asan Institute for Life Sciences, Asan Medical Center (NO: 2017-12-208). The committee abides by the Institute of Laboratory Animal Resources (ILAR) guidelines.

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Yang, G., Kim, YN., Kim, H. et al. Effect of Human Umbilical Cord Matrix-Derived Mesenchymal Stem Cells on Bisphosphonate-Related Osteonecrosis of the Jaw. Tissue Eng Regen Med 18, 975–988 (2021). https://doi.org/10.1007/s13770-021-00372-x

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