Expression of osteoclast differentiation signals by stromal elements of giant cell tumors
Expression of osteoclast differentiation signals by stromal elements of giant cell tumors
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DOI：
10.1359/jbmr.2000.15.4.640
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发表时间：
2000-04-01
影响因子：
6.2
通讯作者：
Findlay, DM
中科院分区：
文献类型：
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作者：
Atkins, GJ;Haynes, DR;Findlay, DM
原发性骨肿瘤引起骨破坏的机制尚未阐明。与大多数其他溶解性骨肿瘤不同，破骨细胞瘤，也称为巨细胞瘤（GCT），在肿瘤基质内含有破骨细胞样细胞。最近鉴定出 TNF-配体超家族的一个新成员，破骨细胞分化因子（ODF/OPGL/RANKL/TRANCE）。 ODF 在 M-CSF 存在下可直接刺激破骨细胞生成。在这项研究中，在许多与体内骨溶解相关的肿瘤样本中检测了 ODF 的表达。此外，我们还研究了破骨细胞前体 RANK 上 ODF 受体的表达，以及 ODF 抑制剂骨保护素 (OPG) 和另一种 TNF 配体超家族成员 TRAIL（之前已证明可以消除 OPG 的抑制作用）。我们在此报告了一项新发现，即 GCT 基质细胞含有丰富的 ODF mRNA，而巨细胞群只表达 RANK mRNA。这些结果与这些肿瘤介导的破骨细胞介导的骨质破坏是一致的。我们还报告了 GCT 样本中 OPG 和 TRAIL mRNA 的表达。与其他骨溶解性和非溶解性肿瘤的比较表明，相对于 OPG mRNA，GCT 表达更多的 ODF 和 TRAIL mRNA。此外，发现GCT表达许多先前报道在破骨细胞生成中发挥核心作用的细胞因子，即IL-1、-6、-11、-17以及TNF-α。重要的是，GCT 还被发现表达高水平的 M-CSF mRNA，这种细胞因子被证明是 ODF 的重要辅助因子，也是成熟和发育中破骨细胞的生存因子。此外，从 GCT 中分离的基质细胞在体外继续表达这些分子。因此，GCT组成型表达目前认为是破骨细胞与前体细胞分化所必需的所有信号。
The mechanisms by which primary tumors of the bone cause bone destruction have not been elucidated. Unlike most other lytic bone tumors, osteoclastomas, otherwise known as giant cell tumors (GCT), contain osteoclast-like cells within the tumor stroma. A new member of the TNF-Iigand superfamily member, osteoclast differentiation factor (ODF/OPGL/RANKL/TRANCE), was recently identified. ODF was shown to directly stimulate osteoclastogenesis, in the presence of M-CSF. In this study, the expression of ODF was examined in a number of tumor samples associated with bone lysis in vivo. In addition, we investigated expression of the ODF receptor on osteoclast precursors, RANK, as web as the ODF inhibitor osteoprotegerin (OPG), and another TNF-ligand superfamily member, TRAIL, previously shown to abrogate the inhibitory effects of OPG. We report here the novel finding that GCT stromal cells contain abundant ODF mRNA, whereas the giant cell population exclusively expresses RANK mRNA. These results are consistent: with the osteoclast-mediated bone destruction by these tumors. We also report the expression of OPG and TRAIL mRNA in GCT samples. A comparison with other lytic and nonlytic tumors of bone showed that GCT express more ODF and TRAIL mRNA relative to OPG mRNA. In addition, GCT were found to express a number of cytokines previously reported to play central roles in osteoclastogenesis, namely, IL-l, -6, -11, -17, as well as TNF-alpha. Importantly, GCT were also found to express high levels of M-CSF mRNA, a cytokine shown to be an essential cofactor of ODF, and a survival factor for mature and developing osteoclasts. Furthermore, expression of these molecules by stromal cells isolated from GCT continued in vitro. Thus GCT constitutively express all of the signals that are currently understood to be necessary for the differentiation of osteoclasts from precursor cells.