Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Bone. 2013 Apr;53(2):487-96. doi: 10.1016/j.bone.2013.01.012. Epub 2013 Jan 17.
Over-expression of the protein Dickkopf-1 (Dkk1) has been associated with multiple myeloma bone disease. Previous reports with the use of anti-Dkk1 neutralizing Ab directed strategies have demonstrated a pro-anabolic effect with associated anti-myeloma activity in 2 in vivo mouse models. However new insights on the role of the wnt pathway in osteoclasts (OC) are emerging and the potential effect of a neutralizing Ab to Dkk1 in osteoclastogenesis remains to be elucidated. In order to better define the effect of an anti-Dkk1 neutralizing Ab on osteoclastogenesis and myeloma, we studied a novel anti-Dkk1 monoclonal Ab in our preclinical models. In vivo data confirmed the pro-anabolic and anti-MM effect. In vitro data in part confirmed the in vivo observation, suggesting an indirect anti-MM effect secondary to inhibition of osteoclastogenesis and thus the interaction between MM and bone microenvironment. However, when studies on osteoclastogenesis were extended to samples derived from MM patients, we observed a variable response to anti-Dkk1 treatment without correlation to expression of surface receptors for Dkk1 in OCs suggesting potential heterogeneity in the efficacy of such a strategy. In conclusion, Dkk1 is a promising target for the treatment of both MM and bone disease, and ongoing clinical studies will help elucidate its efficacy.
蛋白 Dickkopf-1（Dkk1）的过度表达与多发性骨髓瘤骨病有关。使用抗 Dkk1 中和 Ab 定向策略的先前报告表明，在 2 种体内小鼠模型中具有促合成代谢作用，并伴有抗骨髓瘤活性。然而，Wnt 途径在破骨细胞（OC）中的作用的新见解正在出现，中和 Ab 对 Dkk1 在破骨细胞生成中的潜在作用仍有待阐明。为了更好地定义抗 Dkk1 中和 Ab 对破骨细胞生成和骨髓瘤的影响，我们在临床前模型中研究了一种新型抗 Dkk1 单克隆 Ab。体内数据证实了促合成代谢和抗-MM 作用。体外数据部分证实了体内观察结果，表明这是一种间接的抗-MM 作用，继发于破骨细胞生成的抑制，从而导致 MM 与骨微环境之间的相互作用。然而，当将破骨细胞生成研究扩展到源自 MM 患者的样本时，我们观察到抗 Dkk1 治疗的反应存在差异，而与 OC 中 Dkk1 表面受体的表达无关，这表明这种策略的疗效存在潜在异质性。总之，Dkk1 是治疗 MM 和骨病的有前途的靶点，正在进行的临床研究将有助于阐明其疗效。
