Ionizing radiation sensitizes bone cells to apoptosis

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Osteoradionecrosis is a common sequelae of radiation therapy for head and neck cancer. To test the hypothesis that radiation induces osteoradionecrosis by induction of bone cell apoptosis, we exposed MC3T3-E1 osteoblast-like cells to γ-radiation and evaluated cell viability. Twenty-four hours postirradiation, measurement of osteoblast dehydrogenase activity suggested that there was a small decrease in cell viability. However, TUNEL and flow cytometric analysis indicated that the viability loss was caused by inhibition of cell proliferation and not by induction of apoptosis. The effect of irradiation on osteoblast function was examined by Western blot and flow cytometric analysis. It was found that irradiated osteoblasts underwent G2 cell cycle arrest. In addition, we observed changes in expression of molecules that regulate the cell cycle. Thus, there was an increase in p53 transcription, a raised level of MDM2 dephosphorylation, and elevation in p21 and GADD153 protein levels. Since these proteins are concerned with the regulation of the cell cycle, the observed changes in expression would be expected to disturb cyclin activity and cause G2M arrest. The arrested cells displayed a dramatic increase in sensitivity to specific apoptogens. Thus, when irradiated, and then treated with Ca2+Pi or staurosporine, agents that cause mitochondrial dysfunction, more osteoblasts underwent apoptosis than with the apoptogen alone. In contrast, irradiated cells treated with anti-Fas antibody showed no change in apoptotic sensitivity; apoptosis was inhibited when osteoblasts were treated with etoposide. Similar alterations in sensitivity were observed when cells were arrested in G 2/M by pretreatment with colchicine and then challenged with apoptogens. It was concluded that activation of radiation-induced G2 arrest sensitizes osteoblasts to agents that mediate apoptosis through a mitochondrial-dependent death pathway. © 2003 Elsevier Inc. All rights reserved.

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This article was published in Bone, Volume 34, Issue 1, Pages 148-156.

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