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.

中文翻译：

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唑来膦酸盐通过抑制血管内皮生长因子受体2的表达来抑制破骨细胞的分化。

双膦酸盐相关的颌骨坏死（ONJ）是主要的口腔并发症。然而，其发病机理仍不清楚。双膦酸盐对破骨细胞分化的损害可能与ONJ的发病有关。在我们以前的研究中，我们报道了使用编码cDNA的双膦酸盐唑来膦酸盐可将沉默的破骨细胞分化标记活化T细胞c1（NFATc1）的核因子基因的表达显着沉默。芯片。在本研究中，NFATc1基因的表达值被认为是一个临界值，其表达值与NFATc1相比显着降低了在mOCPC中提取基因。为了验证，使用了CD11b阳性（CD11b +）细胞，该细胞是从人外周血单核细胞中纯化的，作为人OCPC。总共鉴定出19个基因。顺序表达分析显示，在CD11b +细胞中，唑来膦酸盐常常使编码血管内皮生长因子受体2（VEGFR2）的基因沉默。此外，使用VEGFR2中和抗体通过VEGFR2抑制，耐酒石酸酸性磷酸酶阳性的多核细胞数量减少。唑来膦酸盐通过抑制VEGFR2表达来抑制人破骨细胞分化。这些结果表明VEGFR2的低表达OCPCs中的氯吡格雷可能参与唑来膦酸盐诱导的ONJ的发病机理。了解VEGFR2在骨骼重塑中的作用对于阐明双膦酸盐相关ONJ的发病机制很重要。