Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma
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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DOI：
10.1182/blood-2008-01-132134
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发表时间：
2008-07-01
期刊：
影响因子：
20.3
通讯作者：
Shaughnessy, John D., Jr.
中科院分区：
文献类型：
--
作者：
Qiang, Ya-Wei;Chen, Yu;Shaughnessy, John D., Jr.
多发性骨髓瘤 (MM) 的特征是溶骨性骨病变 (OBL)，这是由于骨内肿瘤病灶附近的成骨细胞失活和破骨细胞活化而引起的。成骨细胞中的 Wnt 信号通过核因子 Kappa B 配体受体激活剂 (RANKL) 和骨保护素 (OPG) 的差异激活和失活来调节破骨细胞生成，这两种因子分别是破骨细胞分化的正调节剂和负调节剂。我们在此证明，MM 细胞衍生的 DKK1（一种典型 Wnt 信号传导的可溶性抑制剂）会破坏成骨细胞中 Wnt3a 调节的 OPG 和 RANKL 表达。经多项独立测定证实，我们表明用 rDKK1 预处理完全消除了 Wnt3a 诱导的小鼠和人类成骨细胞的 OPG mRNA 和蛋白质产生。此外，我们还发现，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，Wnt3a 诱导的 OPG 表达减少。最后，我们发现来自 21 名 MM 患者的骨髓血清以 DKK1 依赖性方式显着抑制 Wnt3a 诱导的 OPG 表达并增强成骨细胞中的 RANKL 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 比率增加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。
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.