In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma.
In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma.
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DOI：
10.1016/j.bone.2013.01.012
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发表时间：
2013-04
期刊：
影响因子：
4.1
通讯作者：
Raje, Noopur
中科院分区：
文献类型：
--
作者：
Pozzi, Samantha;Fulciniti, Mariateresa;Yan, Hua;Vallet, Sonia;Eda, Homare;Patel, Kishan;Santo, Loredana;Cirstea, Diana;Hideshima, Teru;Schirtzinge, Linda;Kuhstoss, Stuart;Anderson, Kenneth C.;Munshi, Nikhil;Scadden, David;Kronenberg, Henry M.;Raje, Noopur
Dickkopf - 1（Dkk1）蛋白的过度表达与多发性骨髓瘤骨病相关。先前使用抗Dkk1中和抗体导向策略的报告在2个体内小鼠模型中已证明具有促成骨作用以及相关的抗骨髓瘤活性。然而，关于Wnt通路在破骨细胞（OC）中作用的新见解正在不断涌现，并且中和抗体对Dkk1在破骨细胞生成中的潜在作用仍有待阐明。为了更好地确定抗Dkk1中和抗体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单克隆抗体。体内数据证实了促成骨和抗骨髓瘤效应。体外数据在一定程度上证实了体内观察结果，表明在抑制破骨细胞生成以及骨髓瘤与骨微环境之间的相互作用之后产生了间接的抗骨髓瘤效应。然而，当破骨细胞生成的研究扩展到来自骨髓瘤患者的样本时，我们观察到对抗Dkk1治疗的反应不一，且与破骨细胞中Dkk1表面受体的表达无关，这表明这种策略在疗效上可能存在异质性。总之，Dkk1是治疗骨髓瘤和骨病的一个有前景的靶点，正在进行的临床研究将有助于阐明其疗效。
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 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.
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影响因子：
64.8
作者：
Glinka, A;Wu, W;Niehrs, C
通讯作者：
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