Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone
Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone
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DOI：
10.1172/jci11685
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发表时间：
2001-05-01
影响因子：
15.9
通讯作者：
Keller, ET
中科院分区：
文献类型：
--
作者：
Zhang, J;Dai, JL;Keller, ET
前列腺癌（CaP）形成成骨细胞骨骼转移，伴有潜在的破骨细胞成分。然而，破骨细胞发生在CaP骨骼病变发展中的重要性尚不清楚。在本研究中，我们证明了CaP细胞在体外缺乏基质的情况下直接诱导破骨细胞前体发生破骨细胞。CaP细胞产生可溶形式的NF-KB配体受体激活剂（RANKL），这解释了CaP介导的破骨细胞发生。为了评估破骨细胞发生对体内CaP肿瘤发展的重要性，在同一只小鼠体内同时注射CaP细胞，然后给药RANKL的诱捕受体，骨保护素（OPG）。OPG完全阻止了混合溶骨/成骨胫骨肿瘤的形成，正如在载药动物中观察到的那样，但它对皮下肿瘤的生长没有影响。与破骨细胞在肿瘤发展中的作用一致，与opg处理小鼠的正常值相比，车辆处理小鼠骨/肿瘤界面处的破骨细胞数量升高。此外，OPG对体外培养的CaP细胞活力、增殖或基本凋亡率没有影响。这些结果强调了破骨细胞活性在CaP骨转移的建立中发挥的重要作用，包括那些具有成骨细胞成分的骨转移。
Prostate cancer (CaP) forms osteoblastic skeletal metastases with an underlying osteoclastic component. However, the importance of osteoclastogenesis in the development of CaP skeletal lesions is unknown. In the present study, we demonstrate that CaP cells directly induce osteoclastogenesis from osteoclast precursors in the absence of underlying stroma in vitro. CaP cells produced a soluble form of receptor activator of NF-KB ligand (RANKL), which accounted for the CaP-mediated osteoclastogenesis. To evaluate for the importance of osteoclastogenesis on CaP tumor development in vivo, CaP cells were injected both intratibially and subcutaneously in the same mice, followed by administration of the decoy receptor for RANKL, osteoprotegerin (OPG). OPG completely prevented the establishment of mixed osteolytic/osteoblastic tibial tumors, as were observed in vehicle-treated animals, but it had no effect on subcutaneous tumor growth. Consistent with the role of osteoclasts in tumor development, osteoclast numbers were elevated at the bone/tumor interface in the vehicle-treated mice compared with the normal values in the OPG-treated mice. Furthermore, OPG had no effect on CaP cell viability, proliferation, or basal apoptotic rate in vitro. These results emphasize the important role that osteoclast activity plays in the establishment of CaP skeletal metastases, including those with an osteoblastic component.