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首页> 外文期刊>Blood: The Journal of the American Society of Hematology >Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma.
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Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma.

机译：骨髓瘤来源的Dickkopf-1破坏成骨细胞对Wnt调节的骨保护素和RANKL的产生：这是多发性骨髓瘤中溶骨性骨病变的潜在机制。

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摘要

Multiple myeloma (MM) is characterized by osteolytic bone lesions (OBL) that arise as a consequence of osteoblast inactivation and osteoclast activation adjacent to tumor foci within bone. Wnt signaling in osteoblasts regulates osteoclastogenesis through the differential activation and inactivation of Receptor Activator of Nuclear factor Kappa B Ligand (RANKL) and osteoprotegerin (OPG), positive and negative regulators of osteoclast differentiation, respectively. We demonstrate here that MM cell-derived DKK1, a soluble inhibitor of canonical Wnt signaling, disrupted Wnt3a-regulated OPG and RANKL expression in osteoblasts. Confirmed in multiple independent assays, we show that pretreatment with rDKK1 completely abolished Wnt3a-induced OPG mRNA and protein production by mouse and human osteoblasts. In addition, we show that Wnt3a-induced OPG expression was diminished in osteoblasts cocultured with a DKK1-expressing MM cell line or primary MM cells. Finally, we show that bone marrow sera from 21 MM patients significantly suppressed Wnt3a-induced OPG expression and enhanced RANKL expression in osteoblasts in a DKK1-dependent manner. These results suggest that DKK1 may play a key role in the development of MM-associated OBL by directly interrupting Wnt-regulated differentiation of osteoblasts and indirectly increasing osteoclastogenesis via a DKK1-mediated increase in RANKL-to-OPG ratios.
机译：多发性骨髓瘤（MM）的特征是溶骨性骨病变（OBL），这是由于成骨细胞失活和邻近骨内肿瘤灶的破骨细胞活化而引起的。成骨细胞中的Wnt信号通过核因子κB配体（RANKL）和骨保护素（OPG）的激活和失活（破骨细胞分化的正负调节剂）的差异激活和失活来调节破骨细胞的生成。我们在这里证明，MM细胞衍生的DKK1，经典Wnt信号的可溶性抑制剂，破坏了成骨细胞中Wnt3a调节的OPG和RANKL的表达。在多次独立测定中证实，我们显示，用rDKK1进行的预处理完全消除了Wnt3a诱导的小鼠和人类成骨细胞产生的OPG mRNA和蛋白质的产生。此外，我们显示Wnt3a诱导的OPG表达在与表达DKK1的MM细胞系或原代MM细胞共培养的成骨细胞中减少。最后，我们显示了21例MM患者的骨髓血清以DKK1依赖性方式显着抑制了Wnt3a诱导的OPG表达并增强了成骨细胞中RANKL的表达。这些结果表明，DKK1可能通过直接中断Wnt调节的成骨细胞分化并通过DKK1介导的RANKL与OPG比率的增加而间接增加破骨细胞生成，从而在MM相关OBL的发展中发挥关键作用。

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