The effects of bisphosphonates on osteonecrosis of jaw bone: aA stem cell perspective

Bisphosphonates (BPs) are commonly used drugs for the treatment of osteoporosis in routine clinical practice. Although BPs are successfully used for osteoporosis treatment, they may also cause bisphosphonate-induced osteonecrosis of the jaw (BIONJ). Up to present, the researchers have proposed several factors but the effects of BPs on dental stem cells' proliferation, differentiation or maintenance capacity have not been evaluated yet. In current study, the stem cells isolated from dental pulp, periodontal ligament and tooth germ were characterized by specific cell surface marker expression, differentiation and immunostaining assays. Osteogenic differentiation of the Dental Pulp Stem Cells (DPSCs), Periodontal Stem Cells (PDLSCs) and Human Tooth Germ Stem Cells (hTGSCs) treated with Zoledronate (ZOL), Alendronate (ALE) and Risedronate (RIS) were evaluated by mineral staining assays and gene expression analysis. BPs did not cause any negative effect on the osteogenic differentiation of DPSCs, PDLSCs and hTGSCs. Moreover, scratch assay was performed to detect the effects of ZOL, ALE and RIS on migration capacity of these dental stem cells, and migration related genes, extracellular matrix proteins and cytokines were analyzed. The results revealed that all BPs tested significantly inhibited migration ability of the dental tissue-derived stem cells. To evaluate the effects of ZOL, ALE and RIS on angiogenesis, two experimental models, aortic ring and tube formation assays, were performed with human umbilical vein endothelial cells (HUVECs). The results showed that BPs robustly inhibited angiogenic potential of the endothelial cells. The drastic effects of BPs on migration of DPSCs, PDLSCs and TGSCs, and angiogenesis of endothelial cells were determined. Inhibition of the migration capacities of the stem cells localized in proximity to the jaw bone, and interference with angiogenesis process might be the possible explanation for BIONJ observed after BP treatment. Further in vivo studies are highly warranted to investigate dental stem cell conditions in BP treated animals to elucidate the importance of these cells in BIONJ formation.