The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelomatous and nonmyelomatous bones in vivo.
The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelomatous and nonmyelomatous bones in vivo.
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DOI：
10.1002/ajh.21310
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发表时间：
2009-01
影响因子：
12.8
通讯作者：
Yaccoby, Shmuel
中科院分区：
文献类型：
--
作者：
Pennisi, Angela;Li, Xin;Ling, Wen;Khan, Sharmin;Zangari, Maurizio;Yaccoby, Shmuel
多发性骨髓瘤(MM)是一种终末分化的浆细胞恶性血液病，由破骨细胞的刺激和成骨细胞的抑制而诱发的溶骨性骨病的发生密切相关。泛素-蛋白酶体途径调控骨细胞的分化和骨髓瘤细胞的生长。蛋白酶体抑制剂Bortezomib是一种临床上有效的抗骨髓瘤药物。本研究的主要目的是观察硼替佐米对骨髓瘤诱导的骨吸收和16例患者骨髓瘤细胞移植SCID-Rab小鼠肿瘤生长的影响。Bortezomib的抗骨髓瘤效应在16个实验中有50%明显，与临床反应相似，与骨髓瘤骨骼中骨密度(BMD)和成骨细胞数量显著增加，破骨细胞数量减少有关。这种骨合成代谢效应也在X射线片上可见，并经静态和动态组织形态计量学分析证实，这是Bortezomib独有的，在对马法兰(一种广泛用于治疗MM的化疗药物)反应的宿主中没有观察到。Bortezomib还增加了非骨髓瘤植入骨中的BMD和成骨细胞数量，并减少了破骨细胞数量。在体外，Bortezomib直接抑制人破骨细胞的形成，促进成骨细胞的成熟。我们的结论是，Bortezomib通过同时抑制破骨细胞生成和刺激成骨细胞生成，促进骨髓瘤和非骨髓瘤骨的骨形成。临床和实验研究表明，骨病既是多发性骨髓瘤进展的结果，也是多发性骨髓瘤发展的必然结果，我们的结果表明，Bortezomib对骨重塑的影响有助于该药的抗骨髓瘤疗效。
Multiple myeloma (MM), a hematologic malignancy of terminally differentiated plasma cells is closely associated with induction of osteolytic bone disease, induced by stimulation of osteoclastogenesis and suppression of osteoblastogenesis. The ubiquitin-proteasome pathway regulates differentiation of bone cells and MM cell growth. The proteasome inhibitor, bortezomib, is a clinical potent antimyeloma agent. The main goal of this study was to investigate the effect of bortezomib on myeloma-induced bone resorption and tumor growth in SCID-rab mice engrafted with MM cells from 16 patients. Antimyeloma response of bortezomib, which was evident in >50% of 16 experiments and resembled clinical response, was associated with significant increased bone mineral density (BMD) and osteoblast numbers, and reduced osteoclast numbers in myelomatous bones. This bone anabolic effect, which was also visualized on X-ray radiographs and confirmed by static and dynamic histomorphometric analyses, was unique to bortezomib and was not observed in hosts responding to melphalan, a chemotherapeutic drug widely used to treat MM. Bortezomib also increased BMD and osteoblasts number and reduced osteoclasts number in nonmyelomatous implanted bones. In vitro bortezomib directly suppressed human osteoclast formation and promoted maturation of osteoblasts. We conclude that bortezomib promotes bone formation in myelomatous and nonmyelomatous bones by simultaneously inhibiting osteoclastogenesis and stimulating osteoblastogenesis. As clinical and experimental studies indicate that bone disease is both a consequence and necessity of MM progression our results suggest and that bortezomib’s effects on bone remodeling contribute to the antimyeloma efficacy of this drug.
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