Receptor-Activator of Nuclear KappaB Ligand Expression as a New Therapeutic Target in Primary Bone Tumors.
Receptor-Activator of Nuclear KappaB Ligand Expression as a New Therapeutic Target in Primary Bone Tumors.
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DOI：
10.1371/journal.pone.0154680
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Endo N
中科院分区：
文献类型：
--
作者：
Yamagishi T;Kawashima H;Ogose A;Ariizumi T;Sasaki T;Hatano H;Hotta T;Endo N
核κ B配体受体活化因子（RANKL）信号通路在骨生长调节中起重要作用，并介导破骨细胞的形成和活化。破骨细胞参与显著的骨吸收和破坏。Denosumab是一种抗RANKL的全人源单克隆抗体，可特异性抑制破骨细胞分化和骨吸收。它已被批准用于多发性骨髓瘤和骨转移，以及骨巨细胞瘤。然而，没有以前的报告定量比较RANKL表达在组织学上不同的骨肿瘤。因此，我们分析了各种骨肿瘤的mRNA水平，并研究了这些肿瘤作为地舒单抗新治疗靶点的可能性。我们使用实时PCR检测了135例原发性和转移性骨肿瘤临床标本中RANKL mRNA的表达。通过使用RPMI 8226（一种公认表达RANKL的人多发性骨髓瘤细胞系）进行标准化，对mRNA表达水平进行相对定量。在135例病例中，64例还通过免疫组化评价了RANKL表达。在所有研究的肿瘤中，RANKL表达和RANKL/骨保护素比率在骨巨细胞瘤中最高。与多发性骨髓瘤和转移性癌骨病变病例相比，在囊性骨囊肿、纤维异常增殖症、骨肉瘤、软骨肉瘤和内生软骨瘤病例中观察到RANKL mRNA高表达。RANKL阳性基质细胞检测6例：5例GCTB和1例纤维结构不良。当前的研究结果表明，一些原发性骨肿瘤为Denosumab提供了新的治疗靶点，特别是那些表达RANKL的肿瘤和涉及破骨细胞骨吸收的肿瘤。
The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts.