Identification and clinical application of osteoclast-derived growth factors for myeloma

多发性骨髓瘤（MM）几乎完全在骨髓中发展，这表明骨髓微环境支持MM细胞生长和存活。我们发现，破骨细胞（OCs）的MM细胞的生长和存活是有力的增强。尽管OC在与MM细胞共培养时产生的IL-6增加，但抗人IL-6中和抗体仅部分抑制OC的作用。此外，通过膜滤器防止MM细胞和OC之间的细胞接触完全消除了OC效应。因此，OC可能主要通过密切的细胞-细胞相互作用，通过阐述IL-6以外的未知因子来增强MM细胞生长。与破骨细胞生成类似，MM患者骨髓中的血管生成增强，这作为潜在的治疗靶点引起了相当大的关注。我们还发现，OC组成性分泌高水平的血管生成非胶原基质蛋白，骨桥蛋白（OPN），这是已知的协同作用与VEGF的血管生成。条件培养基（CM）从OC增强血管小管的形成，有力的MM细胞。有趣的是，来自两种细胞的共培养物的CM进一步增强了它，表明OC和MM细胞在血管生成中的合作相互作用。抗OPN或VEGF的抗体各自单独部分地和两者组合几乎完全消除了由来自共培养物的CM增强的血管小管形成。因此，OC与MM细胞协同增强血管生成，这在很大程度上是由分别来自OC和MM细胞的OPN和VEGF的协同作用介导的。总的来说，OC不仅可以直接促进MM进展，而且还可以通过增强血管生成来促进MM进展，从而在骨破坏和MM扩张之间形成恶性循环。

Multiple myeloma (MM) almost exclusively develops in the bone marrow, suggesting that the bone marrow microenvironment supports MM cell growth and survival. We found that the growth and survival of MM cells are potently enhanced by osteoclasts (Ocs). The effects of OCs were only partially inhibited by an anti-human IL-6 neutralizing antibody despite the increased production of IL-6 by OCs in co-cultures with MM cells. Furthermore, prevention of a cellular contact between MM cells and OCs by membrane filters completely abolished the OC effect. Therefore, OCs may enhance MM cell growth largely through a close cell-cell interaction by elaborating unknown factor(s) other than IL-6. Similar to osteoclastogenesis, angiogenesis is enhanced in the bone marrow in patients with MM, which has drawn considerable attention as a potential therapeutic target. We also found that OCs constitutively secrete high levels of an angiogenic noncollagenous matrix protein, osteopontin (OPN), which is known to cooperatively act with VEGF in angiogenesis. Conditioned media (CM) from OCs enhanced vascular tubule formation as potently as those from MM cells. Interestingly, CM from co-cultures of both cells further enhanced it, suggesting cooperative interactions between OCs and MM cells in angiogenesis. Antibodies against OPN or VEGF each alone partially and both in combination almost completely abrogated vascular tubule formation enhanced by CM from the co-cultures. Therefore, OCs enhance angiogenesis in concert with MM cells, which is largely mediated by cooperative actions of OPN and VEGF derived from OCs and MM cells, respectively. Collectively, OCs may enhance MM progression not only directly but also through enhanced angiogenesis, thereby forming a vicious cycle between bone destruction and MM expansion.