Bisphosphonates induce osteoblastic cell death through the inhibition of autophagic flux

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  • Tajima Masamichi
    Div. Pharmacol., Dept. Diagnositic and Therapeutic Siences, Meikai Univ. Sch. Dent.

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Other Title
  • ビスホスホネートはオートファジーの流れを阻害することで骨芽細胞死を誘導している

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<p>Extracting teeth of patients treated with bisphosphonates (BPs) occasionally induces the necrosis of jaw (BRONJ), but the cause of disease is still unclear. I found out that the intracellular BP of osteoblastic cells was gradually accumulated in lysosomes. In the present study, I investigated the mechanism of osteoblastic cell death induced by BPs. MC3T3-E1 cells were used as osteoblatic cells. The uptake of BP into cells was observed by fluorescent pamidronate. Apoptosis was evaluated by PSVue 480 and CellEvent caspase 3/7. Formation of autophagosome and autolysosome was observed using DAPGreen and DALGreen respectively. Autophagosome and autolysosome were frequently observed in the cytosol of normal MC3T3-E1 cells. On the other hands, autolysosomes of cells treated with BPs were gradually accumulated around nuclei. The mitochondria of BPs-treated cells were decreased in both response and quantity. Moreover, BPs shrank nuclei of cells. After a while phosphatidylserine (early apoptotic marker) exposed on cell membranes was detected, and finally the activation of caspase 3 was observed. Mitochondria in cells treated with BPs were not co-localized with autolysosomes. These results suggest that BPs may accumulate autolysosome around nuclei of osteoblastic cells, and induce apoptosis due to inhibiting autophagic flux.</p>

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