Imatinib mesylate (Gleevec®) enhances mature osteoclast apoptosis and suppresses osteoclast bone resorbing activity
Imatinib mesylate (Gleevec®) enhances mature osteoclast apoptosis and suppresses osteoclast bone resorbing activity
复制标题
DOI：
10.1016/j.ejphar.2006.09.007
复制
发表时间：
2006-12-03
影响因子：
5
通讯作者：
Kamel, Said
中科院分区：
文献类型：
--
作者：
Dib, Iman El Hajj;Gallet, Marlene;Kamel, Said
最近的研究报道，甲磺酸伊马替尼是一种针对细胞内酪氨酸激酶bcr-abl和血小板衍生生长因子(PDGF)受体的激酶抑制剂，是巨噬细胞集落刺激因子(M-CSF)受体c-FMS的有效抑制剂。鉴于通过c-FMS的M-CSF信号在破骨细胞生物学中发挥重要作用，我们推测伊马替尼阻断这一途径可能会调节破骨细胞的活性。因此，我们利用成熟兔破骨细胞的细胞模型，研究了伊马替尼对体外破骨细胞凋亡和骨吸收活性的影响。我们的研究结果表明，伊马替尼剂量依赖性地刺激破骨细胞凋亡，这一现象可被caspase I抑制剂Z-VAD-Fink阻断。伊马替尼促进破骨细胞死亡的能力伴随着对破骨细胞骨吸收活性的剂量依赖性抑制。伊马替尼还能抑制M-CSF诱导的破骨细胞存活和M-CSF诱导的破骨细胞骨吸收活性，但对白介素1α(IL-1α)和核因子kappa B受体激活剂(RANKL)诱导的破骨细胞凋亡无影响，进一步支持了伊马替尼可能通过抑制c-FMS影响成熟破骨细胞的假说。综上所述，这些结果表明，伊马替尼可能在治疗因过度产生M-CSF而导致骨破坏的疾病中具有临床价值，如骨质疏松症、炎症和肿瘤诱导的骨溶解。(C)2006爱思唯尔B.V.保留所有权利。
Recent studies have reported that imatinib mesylate, a kinase inhibitor that targets the intracellular tyrosine kinase BCR-ABL and the platelet derived growth factor (PDGF) receptor, is an effective inhibitor of the macrophage colony stimulating factor (M-CSF) receptor, c-FMS. Given that M-CSF signalling through c-FMS plays an important role in osteoclast biology, we speculated that blocking such a pathway with imatinib may modulate osteoclast activity. Using a cell model of mature rabbit osteoclasts, we thus investigated the effect of imatinib on in vitro osteoclast apoptosis and bone resorbing activity. Our findings demonstrate that imatinib dose-dependently stimulates osteoclast apoptosis, a phenomenon which is blocked by the caspase I inhibitor Z-VAD-fink. The ability of imatinib to enhance osteoclast cell death was accompanied by a dose-dependent inhibition of osteoclast bone resorbing activity. Imatinib was also found to inhibit M-CSF-induced osteoclast survival as well as M-CSF-induced osteoclast bone resorbing activity, but was without effect on interleukin 1 alpha (IL-1 alpha) and receptor activator of nuclear factor kappa B ligand (RANKL)-induced inhibition of osteoclasts apoptosis, further supporting the hypothesis that imatinib may affect mature osteoclasts through the inhibition of c-FMS. Taken together, these results suggest that imatinib could be of clinical value in treating diseases where bone destruction can occur due to excessive M-CSF production such as osteoporosis, inflammatory-and tumor-induced osteolysis. (c) 2006 Elsevier B.V. All rights reserved.