Politou Marianna C, Heath Deborah J, Rahemtulla Amin, Szydlo Richard, Anagnostopoulos Athanasios, Dimopoulos Meletios A, Croucher Peter I, Terpos Evangelos
Department of Hematology, Faculty of Medicine, Hammersmith Hospital, Imperial College, London, United Kingdom.
Int J Cancer. 2006 Oct 1;119(7):1728-31. doi: 10.1002/ijc.22033.
Dickkopf-1 (DKK-1) protein, a soluble inhibitor of Wnt signalling, has been implicated in the pathogenesis of myeloma bone disease through the suppression of osteoblast differentiation. In this study, serum concentrations of DKK-1 were measured in 50 myeloma patients (32 at diagnosis and 18 before and after autologous stem cell transplantation (ASCT), 18 patients with monoclonal gammopathy of undetermined significance (MGUS), and 22 healthy controls. Serum DKK-1 levels were increased in MM at diagnosis compared with MGUS (mean +/- SD: 67 +/- 54 ng/mL vs. 38 +/- 13 ng/mL; p = 0.006) and controls (31 +/- 11 ng/mL; p = 0.02), while there was no difference between MGUS patients and controls. Although patients with stage 2 and 3 myeloma had higher DKK-1 values than stage 1 patients (79 +/- 63 vs. 40 +/- 13; p = 0.005), no significant correlation between serum DKK-1 and myeloma bone disease was observed. Myeloma patients before ASCT also had increased levels of DKK-1 (63 +/- 77 ng/mL; p = 0.03) compared with controls, supporting the notion that DKK-1 may be responsible for the suppressed osteoblast activity even in patients with low tumor burden. After ASCT, there was a sustained decrease in DKK-1 levels over time, while bone formation markers elevated, suggesting that the reduction of DKK-1 levels after ASCT may correlate with the normalization of osteoblast function. These results could provide the basis for developing agents that block DKK-1, thus restoring osteoblast function and counteracting the increased osteoclastogenesis observed in myeloma.
Dickkopf-1(DKK-1)蛋白是一种Wnt信号通路的可溶性抑制剂,通过抑制成骨细胞分化参与了骨髓瘤骨病的发病机制。在本研究中,检测了50例骨髓瘤患者(32例诊断时、18例自体干细胞移植(ASCT)前后)、18例意义未明的单克隆丙种球蛋白病(MGUS)患者和22例健康对照者的血清DKK-1浓度。与MGUS(平均±标准差:67±54 ng/mL对38±13 ng/mL;p = 0.006)和对照者(31±11 ng/mL;p = 0.02)相比,骨髓瘤诊断时血清DKK-1水平升高,而MGUS患者与对照者之间无差异。虽然2期和3期骨髓瘤患者的DKK-1值高于1期患者(79±63对40±13;p = 0.005),但未观察到血清DKK-1与骨髓瘤骨病之间存在显著相关性。与对照者相比,ASCT前的骨髓瘤患者DKK-1水平也升高(63±77 ng/mL;p = 0.03),这支持了即使在肿瘤负荷较低的患者中DKK-1也可能导致成骨细胞活性受抑制的观点。ASCT后,DKK-1水平随时间持续下降,而成骨标志物升高,提示ASCT后DKK-1水平的降低可能与成骨细胞功能的恢复正常相关。这些结果可为开发阻断DKK-1的药物提供依据,从而恢复成骨细胞功能并对抗骨髓瘤中观察到的破骨细胞生成增加。