Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration
Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration
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DOI：
10.1182/blood-2010-04-279760
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发表时间：
2011-01-27
期刊：
影响因子：
20.3
通讯作者：
Klein, Bernard
中科院分区：
文献类型：
--
作者：
Moreaux, Jerome;Hose, Dirk;Klein, Bernard
多发性骨髓瘤的特征是骨髓中恶性浆细胞（多发性骨髓瘤细胞[MMC]）的克隆扩增。溶骨性骨病变在80%的患者中检测到，因为骨细胞骨吸收增加和成骨细胞骨形成减少。发现MMCs与骨吸收增加的部位密切相关。破骨细胞在体外强烈支持MMC存活。为了进一步阐明破骨细胞/MMC相互作用的机制，我们已经确定了552个基因过表达的破骨细胞与其他骨髓细胞亚群相比。破骨细胞特异性地表达编码4种CCR2靶向趋化因子的基因和编码MMC生长因子的基因。抗CCR2单克隆抗体阻断了MMC的破骨细胞趋化活性，CCR2趋化因子也是MMC生长因子，促进MMC中的丝裂原活化蛋白激酶活化。抗胰岛素生长因子1受体单克隆抗体可完全阻断破骨细胞诱导的MMC存活，抑制破骨细胞和MMC的存活。特异性增殖诱导配体或IL-6抑制剂部分阻断破骨细胞诱导的MMC存活。这些数据可以解释为什么新诊断的MMC表达高水平的CCR 2的患者呈现出许多骨病变。这项研究显示了破骨细胞/MMC相互作用的其他机制，并建议使用CCR2和/或胰岛素生长因子-1靶向策略来阻断这种相互作用并防止耐药性。（血。2011; 117（4）：1280 - 1290）
Multiple myeloma is characterized by the clonal expansion of malignant plasma cells (multiple myeloma cells [MMCs]), in the bone marrow. Osteolytic bone lesions are detected in 80% of patients because of increased osteoclastic bone resorption and reduced osteoblastic bone formation. MMCs are found closely associated with sites of increased bone resorption. Osteoclasts strongly support MMC survival in vitro. To further elucidate the mechanisms involved in osteoclast/MMC interaction, we have identified 552 genes overexpressed in osteoclasts compared with other bone marrow cell subpopulations. Osteoclasts express specifically genes coding for 4 CCR2-targeting chemokines and genes coding for MMC growth factors. An anti-CCR2 monoclonal antibody blocked osteoclast chemoattractant activity for MMC, and CCR2 chemokines are also MMC growth factors, promoting mitogen-activated protein kinase activation in MMC. An anti-insulin growth factor-1 receptor monoclonal antibody completely blocked the osteoclast-induced survival of MMC suppressing both osteoclast and MMC survival. Specific a proliferation-inducing ligand or IL-6 inhibitors partially blocked osteoclast-induced MMC survival. These data may explain why newly diagnosed patients whose MMC express high levels of CCR2 present numerous bone lesions. This study displays additional mechanisms involved in osteoclast/MMC interaction and suggests using CCR2 and/or insulin growth factor-1 targeting strategies to block this interaction and prevent drug resistance. (Blood. 2011;117(4):1280-1290)