Osteocytic cell necrosis is caused by a combination of glucocorticoid-induced Dickkopf-1 and hypoxia
Osteocytic cell necrosis is caused by a combination of glucocorticoid-induced Dickkopf-1 and hypoxia
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DOI：
10.1007/s00795-014-0077-9
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发表时间：
2015-06-01
影响因子：
1.8
通讯作者：
Matsumoto, Tadami
中科院分区：
文献类型：
--
作者：
Ueda, Shusuke;Ichiseki, Toru;Matsumoto, Tadami
骨坏死是骨科领域中糖皮质激素引起的主要并发症。尽管有广泛的研究，糖皮质激素诱导的骨坏死的机制在很大程度上是未知的。在这里，我们首先提供的证据表明，联合治疗培养的骨细胞与糖皮质激素和缺氧引起坏死细胞死亡，这是假设发生在急性骨损伤糖皮质激素诱导。我们培养的MLO-Y 4小鼠骨细胞缺氧地塞米松（Dex）的存在或不存在下，并检查凋亡和坏死细胞死亡的比率。单独使用地塞米松或缺氧会增加细胞凋亡，但不会增加坏死细胞。Dex和缺氧的组合显著增加骨细胞死亡，特别是坏死细胞死亡。Dickkopf-1（Dkk-1）是Wnt/β-catenin信号的抑制剂，其表达在对照和缺氧细胞中几乎不表达，但在Dex处理的细胞中检测到Dkk-1表达的显著增加。siRNA介导的Dkk-1在Dex和缺氧处理的骨细胞中的敲低显示凋亡和坏死细胞的显著减少。结果表明，Dex诱导的Dkk-1过表达和缺氧联合作用导致坏死性骨细胞死亡。阻断Dkk-1表达可保护骨细胞免受糖皮质激素和缺氧诱导的细胞损伤。
Osteonecrosis is a major glucocorticoid-induced complication in the orthopedics field. Despite the extensive researches, mechanisms underlining the glucocorticoid-induced osteonecrosis are largely unknown. Here, we first provide the evidence that a combined treatment of cultured osteocytic cells with glucocorticoid and hypoxia caused necrotic cell death, which is assumed to occur in the acute bone injuries induced by glucocorticoids. We cultured MLO-Y4 murine osteocytic cells under hypoxia in the presence or absence of Dexamethasone (Dex) and examined the rates of apoptotic and necrotic cell death. Dex or hypoxia alone increased apoptotic cells, but not necrotic cells. The combination of Dex and hypoxia dramatically increased osteocytic cell death, notably necrotic cell death. The expression of Dickkopf-1 (Dkk-1), an inhibitor of Wnt/beta-catenin signal, was scarcely expressed in the control and hypoxic cells, but a dramatic increase of the Dkk-1 expression was detected in Dex-treated cells. siRNA-mediated knockdown of Dkk-1 in Dex and hypoxia-treated osteocytic cells showed the significant decreases in both apoptotic and necrotic cells. The results indicated that the combination of Dkk-1 overexpression by Dex and hypoxia causes the necrotic osteocytic cell death. The results also indicated that blocking of Dkk-1 can protect bone cells from glucocorticoid and hypoxia-induced cell injury.