Bisphosphonates (BPs) are widely used for the prevention and treatment of osteoporosis. However, there have been numerous reports of side effects of BPs, including osteonecrosis of the jaw. In the present study, we investigated whether hypoxia inhibits BP-induced apoptosis, and examined the mechanisms of this inhibition. The cell viability of the MG 63 human osteoblast-like cell line treated with the nitrogen-containing (N)-BPs alendronate, risedronate and zoledronate was investigated, and hypoxia was assessed by crystal violet staining and the MTT assay, and by observing cell morphology. The effect of N-BPs and hypoxia on apoptotic cell signaling was evaluated using Western blotting, immunocytochemistry and the TUNEL assay. The results of crystal violet staining and the MTT and TUNEL assays showed that the N-BPs inhibited proliferation and induced apoptosis in MG 63 cells. Hypoxia significantly prevented N-BP-induced MG 63 cell apoptosis, and also attenuated BP-induced c-Jun N-terminal kinase (JNK) phosphorylation and BCL-xL reduction. Hypoxia prevented BP-induced cell damage by blocking JNK phosphorylation and by regulating the BCL-xL protein. Thus, hypoxia or hypoxia-related genes, including hypoxia-inducible factor 1α, may be a potential therapy for BP-related side effects such as osteonecrosis of the jaw.

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