Gwanghyun Yang1, Young-Nam Kim1, Hyunjeong Kim1, Bu-Kyu Lee2,3. 1. Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea. 2. Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea. bukyu.lee@gmail.com. 3. Department of Oral and Maxillofacial Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea. bukyu.lee@gmail.com.
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.
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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