MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts
MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts
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DOI：
10.1182/blood-2007-05-093294
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发表时间：
2007-11-15
期刊：
影响因子：
20.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Vallet, Sonia;Raje, Noopur;Anderson, Kenneth C.
破骨细胞（OCs）与多发性骨髓瘤（MM）细胞之间的相互作用在MM相关的溶骨性骨病的发病机制中起着关键作用（01313）。MM细胞促进OC的形成，OC反过来又促进MM细胞的增殖。趋化因子是MM对骨作用的介质，反之亦然；特别是CCL3可以促进OC的形成，促进MM细胞的迁移和存活。在这里，我们描述了趋化因子受体CCR1的新型特异性拮抗剂MLN3897对OC形成和OC- mm细胞相互作用的影响。MLN3897显示出OC形成（40%）和功能（70%）的显著损伤，与前体细胞多核减少和c-fos信号的下调有关。OCs分泌高水平的CCL3，触发MM细胞迁移；相反，MLN3897通过抑制Akt信号通路来消除其作用。此外，MLN3897可消除MM细胞与oc的粘附，从而抑制MM细胞的存活和增殖。因此，我们的研究结果显示了CCL3的新的生物学后遗症及其对破骨细胞发生和MM细胞生长的抑制作用，为MLN3897治疗MM OBD的临床试验提供了临床前依据。
The interaction between osteoclasts (OCs) and multiple myeloma (MM) cells plays a key role in the pathogenesis of MM-related osteolytic bone disease (01313). MM cells promote OC formation and, in turn, OCs enhance MM cell proliferation. Chemokines are mediators of MM effects on bone and vice versa; in particular, CCL3 enhances OC formation and promotes MM cell migration and survival. Here, we characterize the effects of MLN3897, a novel specific antagonist of the chemokine receptor CCR1, on both OC formation and OC-MM cell interactions. MLN3897 demonstrates significant impairment of OC formation (by 40%) and function (by 70%), associated with decreased precursor cell multinucleation and down-regulation of c-fos signaling. OCs secrete high levels of CCL3, which triggers MM cell migration; conversely, MLN3897 abrogates its effects by inhibiting Akt signaling. Moreover, MM cell-to-OC adhesion was abrogated by MLN3897, thereby inhibiting MM cell survival and proliferation. Our results therefore show novel biologic sequelae of CCL3 and its inhibition in both osteoclastogenesis and MM cell growth, providing the preclinical rationale for clinical trials of MLN3897 to treat OBD in MM.