Genome-wide screening of target genes of BRONJ

BRONJ靶基因全基因组筛选

• 批准号: 23792347
• 负责人: NAKAGAWA Takayuki
• 金额: $ 2.66万
• 依托单位: Hiroshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23792347/
• 关键词: 口腔外科学一般; マイクロアレイ

Objective. RANKL inhibitors, denosmab is recently available for use replace to bisphosphonates (BPs). However, the appearance frequency of osteonecrosis of jaw (ONJ) in denosmab treated patients is about the same as BPs. This evidence suggests that the inhibition of RANKL-mediated osteoclastogenesis may have close relationship with the outbreak of ONJ. According to this hypothesis, this study was designed to evaluate the effect of zoledronate on RANKL-mediated osteoclastogenesis and to investigate the molecular targets of zoledronate in RANKL-inducible genes. Methods. The direct effect of zoledronate on osteoclast differentiation was investigated using an in vitro culture system of osteoclast precursor cells stimulated with RANKL and M-CSF. The molecular targets of zoledronate in RANKL signal pathway and additional factors associated with osteoclastogenesis were analyzed by genome-widescreening. Results. Zoledronate reduced the formation of TRAP-positive multi-nucleated cells induced by RANKL treatment. Microarray analysis identified that 2 genes, nuclearfactor of activated T cells c1 (NFATc1) and carbonic anhydrase 2 (Car2), were silenced in zoledronate treated cells among RANKL-inducible genes and additional factors. Two genes, NFATc1 and Car2 were significantly silenced by zoledronate treatment. Conclusion. Zoledronate inhibited RANKL-mediated osteoclastogenesis. In addition, the expression of NFATc1 and Car2 is strongly suppressed by zoledronate. Our result suggests that these genes are possible targets of zolodronate in RANKL-mediated osteoclastogenesis

客观的。 RANKL 抑制剂 denosmab 最近可用于替代双膦酸盐 (BP)。然而，使用 densmab 治疗的患者中颌骨坏死 (ONJ) 的出现频率与 BP 大致相同。这一证据表明，RANKL介导的破骨细胞生成的抑制可能与ONJ的爆发有密切关系。根据这一假设，本研究旨在评估唑来膦酸对RANKL介导的破骨细胞生成的影响，并研究唑来膦酸在RANKL诱导基因中的分子靶点。方法。使用 RANKL 和 M-CSF 刺激的破骨细胞前体细胞体外培养系统研究了唑来膦酸对破骨细胞分化的直接影响。通过全基因组筛选分析了 RANKL 信号通路中唑来膦酸的分子靶点以及与破骨细胞生成相关的其他因素。结果。唑来膦酸减少 RANKL 处理诱导的 TRAP 阳性多核细胞的形成。微阵列分析发现，在 RANKL 诱导基因和其他因子中，唑来膦酸盐处理的细胞中，有 2 个基因被沉默，即活化 T 细胞核因子 c1 (NFATc1) 和碳酸酐酶 2 (Car2)。唑来膦酸盐处理显着沉默了两个基因 NFATc1 和 Car2。结论。唑来膦酸抑制 RANKL 介导的破骨细胞生成。此外，唑来膦酸强烈抑制 NFATc1 和 Car2 的表达。我们的结果表明这些基因可能是 RANKL 介导的破骨细胞生成中唑洛膦酸的靶标