A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies.
A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies.
复制标题
DKK-1在骨肉瘤发病机理中的潜在作用预测了新颖的诊断和治疗策略。
DOI：
10.1038/sj.bjc.6604069
复制
发表时间：
2007-12-03
影响因子：
8.8
通讯作者：
Gregory, C A
中科院分区：
文献类型：
--
作者：
Lee, N;Smolarz, A J;Olson, S;David, O;Reiser, J;Kutner, R;Daw, N C;Prockop, D J;Horwitz, E M;Gregory, C A
规范的Wnt信号是一种骨诱导信号，通过促进祖细胞的成骨分化来促进骨修复。DKK-1是典型的Wnt信号的分泌型抑制物，从而抑制成骨。为了检测DKK-1在骨肉瘤(OS)中的潜在骨抑制作用，我们检测了OS(中位年龄，13.4岁)儿童患者的血清DKK-1，发现其显著升高。我们还发现，DKK-1在肿瘤周边的OS细胞中表达最高，在体外，DKK-1和RANKL在快速增殖的OS细胞中共同表达。DKK-1和OS细胞的条件培养液均可减少人骨髓间充质细胞的成骨，并通过免疫耗竭DKK-1或加入GSK3β抑制剂来减弱DKK-1的作用。在小鼠身上，我们发现植入肿瘤的DKK-1的表达类似于人类肿瘤活检组织，因为在受体动物的血清中存在人DKK-1。这些数据表明，在OS中，DKK-1的系统水平升高。此外，DKK-1在肿瘤周边的OS细胞的表达可能通过抑制周围骨骼的修复而促进肿瘤的扩张。这些数据表明，DKK-1可作为评估OS的预后或诊断标志物，此外，免疫耗竭DKK-1或给予GSK3β抑制剂可作为该病的辅助治疗。
Canonical Wnt signalling is an osteoinductive signal that promotes bone repair through acceleration of osteogenic differentiation by progenitors. Dkk-1 is a secreted inhibitor of canonical Wnt signalling and thus inhibits osteogenesis. To examine a potential osteoinhibitory role of Dkk-1 in osteosarcoma (OS), we measured serum Dkk-1 in paediatric patients with OS (median age, 13.4 years) and found it to be significantly elevated. We also found that Dkk-1 was maximally expressed by the OS cells at the tumour periphery and in vitro, Dkk-1 and RANKL are coexpressed by rapidly proliferating OS cells. Both Dkk-1 and conditioned media from OS cells reduce osteogenesis by human mesenchymal cells and by immunodepletion of Dkk-1, or by adding a GSK3β inhibitor, the effects of Dkk-1 were attenuated. In mice, we found that the expression of Dkk-1 from implanted tumours was similar to the human tumour biopsies in that human Dkk-1 was present in the serum of recipient animals. These data demonstrate that systemic levels of Dkk-1 are elevated in OS. Furthermore, the expression of Dkk-1 by the OS cells at the periphery of the tumour probably contributes to its expansion by inhibiting repair of the surrounding bone. These data demonstrate that Dkk-1 may serve as a prognostic or diagnostic marker for evaluation of OS and furthermore, immunodepletion of Dkk-1 or administration of GSK3β inhibitors could represent an adjunct therapy for this disease.