文章：

骨髓瘤细胞通过分泌硬化蛋白抑制成骨细胞

Myeloma cells suppress osteoblasts through sclerostin secretion

原文发布日期：2011-06-24

DOI: 10.1038/bcj.2011.22

类型: Original Article

开放获取: 是

英文摘要：

Wingless-type (Wnt) signaling through the secretion of Wnt inhibitors Dickkopf1, soluble frizzled-related protein-2 and -3 has a key role in the decreased osteoblast (OB) activity associated with multiple myeloma (MM) bone disease. We provide evidence that another Wnt antagonist, sclerostin, an osteocyte-expressed negative regulator of bone formation, is expressed by myeloma cells, that is, human myeloma cell lines (HMCLs) and plasma cells (CD138+ cells) obtained from the bone marrow (BM) of a large number of MM patients with bone disease. We demonstrated that BM stromal cells (BMSCs), differentiated into OBs and co-cultured with HMCLs showed, compared with BMSCs alone, reduced expression of major osteoblastic-specific proteins, decreased mineralized nodule formation and attenuated the expression of members of the activator protein 1 transcription factor family (Fra-1, Fra-2 and Jun-D). Moreover, in the same co-culture system, the addition of neutralizing anti-sclerostin antibodies restored OB functions by inducing nuclear accumulation of β-catenin. We further demonstrated that the upregulation of receptor activator of nuclear factor κ-B ligand and the downregulation of osteoprotegerin in OBs were also sclerostin mediated. Our data indicated that sclerostin secretion by myeloma cells contribute to the suppression of bone formation in the osteolytic bone disease associated to MM.

摘要翻译： 

通过分泌Wnt抑制剂Dickkopf1、可溶性卷曲相关蛋白-2和-3，Wnt信号通路在多发性骨髓瘤骨病相关的成骨细胞活性减弱中起关键作用。我们证实另一种Wnt拮抗剂硬化蛋白（一种由骨细胞表达的骨形成负向调节因子）可由骨髓瘤细胞表达，即来自大量伴发骨病的多发性骨髓瘤患者骨髓中获取的人骨髓瘤细胞系和浆细胞（CD138+细胞）。研究显示，与单独培养相比，分化成成骨细胞并与人骨髓瘤细胞系共培养的骨髓基质细胞中：成骨细胞特异性主要蛋白表达降低、矿化结节形成减少、激活蛋白1转录因子家族成员（Fra-1、Fra-2和Jun-D）表达减弱。此外，在同一共培养体系中，添加中和性抗硬化蛋白抗体可通过诱导β-连环蛋白核聚集来恢复成骨细胞功能。我们进一步证实成骨细胞中核因子κB受体活化因子配体的上调和骨保护素的下调也由硬化蛋白介导。我们的数据表明，骨髓瘤细胞分泌的硬化蛋白有助于抑制与多发性骨髓瘤相关的溶骨性骨病中的骨形成。

原文链接：

Myeloma cells suppress osteoblasts through sclerostin secretion