Roato Ilaria, Grano Maria, Brunetti Giacomina, Colucci Silvia, Mussa Antonio, Bertetto Oscar, Ferracini Riccardo
Center for Experimental Research and Medical Studies, University and A.S.O. San Giovanni Battista, Turin, Italy.
FASEB J. 2005 Feb;19(2):228-30. doi: 10.1096/fj.04-1823fje. Epub 2004 Nov 18.
Bone metastases represents a common cause of morbidity in patients suffering many types of cancer: breast, lung, kidney, prostate, and multiple myeloma. Osteolytic metastases often cause severe pain, pathologic fractures, hypercalcemia, spinal cord compression, and other nerve-compression syndromes. Osteoclasts (OCs), cells deriving from granulocitic-macrophagic lineage, are responsible for osteolysis, which may be reduced by inhibiting both OCs formation and activity. By studying bone osteolytic metastases mechanism in solid tumors, we report here our findings that cancer patients with bone involvement display an increase in osteoclasts precursors, compared with both healthy controls and cancer patients without bone metastases. Peripheral blood mononuclear cells (PBMCs) from patients with osteolytic lesions show osteoclastogenesis without adding M-CSF, RANKL, or TNF-alpha. However, these factors are necessary to generate OCs from healthy donors, non-osteolytic patient PBMCs and T-cell depleted PBMCs. OCs derived from cancer patients show more resorption pits than OCs from healthy donors and express genes involved in osteoclastogenesis. Our data show that a spontaneous osteoclastogenesis occurs in patients affected by osteolytic lesions and may be supported by factors released by T lymphocytes. These factors could give a priming to osteoclast precursors and promote osteoclastogenesis. In fact, T-cell depleted PBMCs do not differentiate into OCs without adding M-CSF and RANKL. Moreover, we do not obtain a higher number of OCs by increasing RANKL doses in cultures, and OCs and T lymphocytes mRNA level are detected for TNF-alpha but not for RANKL. The addition of OPG to PBMCs cultures do not modify spontaneous osteoclastogenesis. A neutralizing anti-TNF-alpha antibody in unstimulated PBMC cultures of osteolytic cancer patients induces an inhibition of osteoclastogenesis. These data suggest that TNF-alpha may be responsible for osteoclastogenesis in these tumors.
骨转移是多种癌症患者发病的常见原因，这些癌症包括乳腺癌、肺癌、肾癌、前列腺癌和多发性骨髓瘤。溶骨性转移通常会导致严重疼痛、病理性骨折、高钙血症、脊髓压迫和其他神经压迫综合征。破骨细胞（OCs）来源于粒细胞-巨噬细胞谱系，负责骨溶解，抑制破骨细胞的形成和活性可减少骨溶解。通过研究实体瘤中的骨溶骨性转移机制，我们在此报告我们的发现：与健康对照组和无骨转移的癌症患者相比，有骨转移的癌症患者破骨细胞前体增加。来自溶骨性病变患者的外周血单核细胞（PBMCs）在不添加M-CSF、RANKL或TNF-α的情况下即可显示破骨细胞生成。然而，从健康供体、非溶骨性患者的PBMCs和T细胞耗竭的PBMCs生成破骨细胞则需要这些因子。与健康供体的破骨细胞相比，来自癌症患者的破骨细胞显示出更多的吸收陷窝，并表达参与破骨细胞生成的基因。我们的数据表明，溶骨性病变患者会发生自发破骨细胞生成，这可能由T淋巴细胞释放的因子所支持。这些因子可能会启动破骨细胞前体并促进破骨细胞生成。事实上，T细胞耗竭的PBMCs在不添加M-CSF和RANKL的情况下不会分化为破骨细胞。此外，我们在培养物中增加RANKL剂量时并未获得更多的破骨细胞，并且检测到破骨细胞和T淋巴细胞的mRNA水平与TNF-α有关，而与RANKL无关。向PBMCs培养物中添加OPG不会改变自发破骨细胞生成。在溶骨性癌症患者未受刺激的PBMC培养物中加入中和性抗TNF-α抗体可抑制破骨细胞生成。这些数据表明，TNF-α可能是这些肿瘤中破骨细胞生成的原因。
