Effect of human umbilical cord dervied MSCs on bisphosphonate-related ostenecrosis of the jaw

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. Conclusions: 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.