Bortezomib inhibits maturation and function of osteoclasts from PBMCs of patients with multiple myeloma by downregulating TRAF6
Bortezomib inhibits maturation and function of osteoclasts from PBMCs of patients with multiple myeloma by downregulating TRAF6
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DOI：
10.1016/j.leukres.2008.07.028
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发表时间：
2009-01-01
影响因子：
2.7
通讯作者：
Hou Han
中科院分区：
文献类型：
--
作者：
Huang Hongming;Hou Han
多发性骨髓瘤（MM）与破骨细胞活化增加相关，导致骨降解增强和溶解性骨病变形成。本研究观察硼替佐米对MM患者外周血单个核细胞（PBMCs）破骨细胞成熟和功能的抑制作用，试图阐明硼替佐米对破骨细胞生成的上游分子机制。在存在NF-κ B B配体受体激活剂（RANKL）和巨噬细胞集落刺激因子（M-CSF）的情况下培养8例MM患者PBMC中的破骨细胞前体。施用2.5和5 nM硼替佐米导致破骨细胞分化减少，破骨细胞形成减少，TRAP活性水平降低。破骨细胞吸收能力也降低，表明硼替佐米能够抑制破骨细胞的功能。Western-blot和RT-PCR检测结果表明硼替佐米通过在蛋白和mRNA水平上降低TRAF 6的产生来抑制破骨细胞。总之，硼替佐米在低浓度下通过干扰TRAF 6的产生来作用于破骨细胞生成，这可能被证明是治疗骨髓瘤骨病的潜在策略。(C)2008爱思唯尔有限公司保留所有权利。
Multiple myeloma (MM) is associated with increased activation of osteoclasts, causing enhanced bone degradation and formation of lytic bone lesions. In this study, we observed the inhibitory effect of bortezomib on osteoclasts; maturation and function from peripheral blood mononuclear cells (PBMCs) of MM patients, in an attempt to clarify the upstream molecular mechanism of bortezomib on osteoclastogenesis. Osteoclast precursors from PBMCs of eight MM patients were cultured in the presence of receptor activator of NF-kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). Administration of 2.5 and 5 nM bortezomib resulted in the reduction of osteoclast differentiation by less formation of osteoclasts and the decreased activity level of TRAP. Osteoclast resorption capacity also decreased, suggesting that bortezomib was able to inhibit the function of osteoclasts. The results of Western-blot and RT-PCR assays suggested that bortezomib inhibited osteoclasts by decreasing TRAF6 production at both protein and mRNA levels. In conclusion, bortezomib acts on osteoclastgenesis at low concentrations by interfering with TRAF6 production, which might prove to be a potential strategy for the treatment of myeloma bone disease. (C) 2008 Elsevier Ltd. All rights reserved.