Zoledronate Inhibits Osteoclast Differentiation via Suppressing Vascular Endothelial Growth Factor Receptor 2 Expression
Zoledronate Inhibits Osteoclast Differentiation via Suppressing Vascular Endothelial Growth Factor Receptor 2 Expression
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唑来膦酸钠通过抑制血管内皮生长因子受体2表达抑制破骨细胞分化
DOI：
10.1007/s10528-020-09961-2
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发表时间：
2020-06-01
影响因子：
2.4
通讯作者：
Takechi, Masaaki
中科院分区：
文献类型：
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作者：
Nakagawa, Takayuki;Ohta, Kouji;Takechi, Masaaki
双磷酸盐相关性颌骨骨坏死（ONJ）是一种主要的口腔并发症，然而，其发病机制仍不清楚。双磷酸盐对破骨细胞分化的损害可能与ONJ的发病机制有关。在我们以前的研究中，我们报道了基因编码的核因子活化T细胞c1（NFATc 1），一个已知的破骨细胞分化标志物，显着沉默唑来膦酸盐，二膦酸盐，在小鼠破骨细胞前体细胞（mOCPCs）的cDNA微阵列。在本研究中，将NFATc 1基因的表达值视为截止值，提取mOCPC中与NFATc 1基因相比表达值显著降低的基因。为了验证，使用了从人外周血单核细胞中纯化的CD 11b阳性（CD 11b+）细胞作为人OCPC。共鉴定了19个基因;序列表达分析显示，在CD 11b+细胞中，唑来膦酸盐经常沉默编码血管内皮生长因子受体2（VEGFR 2）的基因。此外，使用VEGFR 2中和抗体抑制VEGFR 2可减少抗酒石酸酸性磷酸酶阳性多核细胞的数量。唑来膦酸通过抑制VEGFR 2表达抑制人破骨细胞分化。这些结果表明，VEGFR 2在OCPC中的低表达可能参与了唑来膦酸诱导的ONJ的发病机制。了解VEGFR 2在骨重建中的作用对于阐明二膦酸盐相关ONJ的发病机制具有重要意义。
Bisphosphonate-related osteonecrosis of the jaw (ONJ) is a major oral complication; however, its pathogenesis remains unclear. Impairment of osteoclast differentiation by bisphosphonates may be associated with the pathogenesis of ONJ. In our previous study, we reported that the expression of the gene encoding nuclear factor of activated T cells c1 (NFATc1), a known osteoclast differentiation marker, was significantly silenced by zoledronate, a bisphosphonate, in mouse osteoclast precursor cells (mOCPCs) using cDNA microarray. In the present study, the expression value of the NFATc1 gene was regarded as a cut-off and genes whose expression value was significantly decreased compared with that of the NFATc1 gene were extracted in mOCPCs. For validation, CD11b-positive (CD11b+) cells were used, which were purified from human peripheral blood mononuclear cells as human OCPCs. A total of 19 genes were identified; sequential expression analysis revealed that the gene encoding vascular endothelial growth factor receptor 2 (VEGFR2) was frequently silenced by zoledronate in CD11b+ cells. Furthermore, the number of tartrate-resistant acid phosphatase-positive multinucleated cells was decreased by VEGFR2 suppression using a VEGFR2 neutralizing antibody. Zoledronate inhibits human osteoclast differentiation via suppressing VEGFR2 expression. These results suggest that low expression of VEGFR2 in OCPCs may be involved in the pathogenesis of zoledronate-induced ONJ. The understanding of the role of VEGFR2 on bone remodeling is important to elucidate the pathogenesis of bisphosphonate-related ONJ.