The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients
The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients
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DOI：
10.1182/blood-2006-11-059188
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发表时间：
2007-07-01
期刊：
影响因子：
20.3
通讯作者：
Rizzoli, Vittorio
中科院分区：
文献类型：
--
作者：
Giuliani, Nicola;Morandi, Francesca;Rizzoli, Vittorio
蛋白酶体抑制剂硼替佐米可能会增加多发性骨髓瘤（MM）患者的成骨细胞相关标志物;然而，其潜在的成骨细胞刺激作用尚不清楚。在这项研究中，我们发现硼替佐米对人间充质细胞中的成骨细胞标志物具有显著的刺激作用，而不影响骨髓培养物中成骨祖细胞的数量或成熟成骨细胞的活力。因此，我们发现硼替佐米显著增加人成骨细胞祖细胞和成骨细胞中转录因子Runx 2/Cbfa 1的活性，而不影响核和细胞质活性β-连环蛋白水平。因此，在成骨细胞祖细胞中也证实了硼替佐米对骨结节形成的刺激作用。这些体外观察结果在体内得到了证实，在对硼替佐米有反应的MM患者中观察到成骨细胞数量x mm（2）骨组织和Runx 2/Cbfa 1阳性成骨细胞数量显著增加。我们的体外和体内观察结果支持硼替佐米治疗期间可能对骨形成过程产生直接刺激作用的假设。
The proteasome inhibitor bortezomib may increase osteoblast-related markers in multiple myeloma (MM) patients; however, its potential osteoblastic stimulatory effect is not known. In this study, we show that bortezomib significantly Induced a stimulatory effect on osteoblast markers in human mesenchymal cells without affecting the number of osteoblast progenitors in bone marrow cultures or the viability of mature osteoblasts. Consistently we found that bortezomib significantly increased the transcription factor Runx2/Cbfa1 activity in human osteoblast progenitors and osteoblasts without affecting nuclear and cytoplasmatic active p-catenin levels. Consequently a stimulatory effect of bortezomib on bone nodule formation was also demonstrated in osteoblast progenitors. These In vitro observations were confirmed in vivo by the finding of a significant increase in the number of osteoblastic cells x mm(2) of bone tissue and in the number of Runx2/Cbfa1-posltlve osteoblastic cells that was observed In MM patients who responded to bortezomib. Our In vitro and In vivo observations support the hypothesis that a direct stimulatory effect on bone formation process could occur during bortezomib treatment.