文章：

Notch通路抑制控制小鼠MOPC315.BM模型中的骨髓瘤骨病

Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model

原文发布日期：2014-06-13

DOI: 10.1038/bcj.2014.37

类型: Original Article

开放获取: 是

英文摘要：

Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-κB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM.

摘要翻译： 

尽管有证据表明，失调的Notch信号通路是多发性骨髓瘤发病机制的主要调节因子，但其在骨髓瘤骨病中的作用尚待阐明。Notch在体外能促进人多发性骨髓瘤细胞的存活并激发人破骨细胞活性。本研究显示，通过γ-分泌酶抑制剂XII抑制Notch可诱导具有高Notch活性的小鼠MOPC315.BM骨髓瘤细胞凋亡。GSI XII在体外可抑制NF-κB配体受体激活剂刺激的RAW264.7细胞向小鼠破骨细胞分化。在小鼠MOPC315.BM骨髓瘤模型中，GSI XII具有强大的抗多发性骨髓瘤活性，并减少溶骨性病变——这通过降低骨髓瘤特异性单克隆免疫球蛋白A血清水平，以及通过高分辨率微型计算机断层扫描对骨结构变化进行定量评估来证实。因此，我们认为GSI XII通过抑制Notch来控制骨髓瘤骨病，主要是通过靶向多发性骨髓瘤细胞及其微环境中的破骨细胞实现的。我们得出结论：Notch抑制是多发性骨髓瘤的一种有效治疗策略。

原文链接：

Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model