NIK, osteoclastogenesis, and osteolytic bone metastasis

描述（由申请人提供）： 溶骨性骨转移是许多癌症的显著特征，包括乳腺癌、前列腺癌、甲状腺癌和肺癌。这些转移通过增加破骨细胞活性和分化驱动过度的骨吸收。最近的研究表明，RANKL/RANK通路对破骨细胞的发育至关重要，RANK是溶骨性骨转移形成所必需的。我的小组的工作揭示了由NF-κ B诱导激酶（NIK）控制的RANK/RANKL通路的另一个分支。尽管NIK缺陷小鼠表现出正常的破骨细胞数量、骨结构和骨发育，但当注射RANKL或PTH时，它们未能产生破骨细胞生成反应，所述RANKL或PTH通过上调RANKL起作用。此外，来自NIK-/-小鼠的破骨细胞前体在体外不能响应RANKL而形成破骨细胞。然而，相比之下，来自NIK-/-小鼠的祖细胞在体外与TNF α和/或TGF β一起呈递时可以形成破骨细胞。本研究的主要目的是确定破骨细胞分化的NIK依赖性途径，并确定参与该途径的蛋白质（包括NIK）是否是骨转移的相关治疗靶点。我们假设： 1.破骨细胞生成过程中RANKL控制的基因网络在NIK-/-培养物中受到干扰，并通过TGF β/TNF α治疗正常化。 2.保护NIK-/-小鼠免于溶骨性骨转移。 因此，我们的具体目标是： 1.使用基因表达谱来定义破骨细胞生成过程中受RANKL控制的基因网络，这些基因在NIK-/-培养物中受到干扰，并通过TGF β/TNF α治疗恢复。 2.确定NIK-/-小鼠在多种形式的溶骨性骨转移中是否受到骨病变的保护。

DESCRIPTION (provided by applicant): Osteolytic bone metastasis is a prominent feature of many cancers including those of the breast, prostate, thyroid and lung. These metastases drive excessive bone resorption by increasing osteoclast activity and differentiation. Recent work has shown that the RANKL/RANK pathway is critical to osteoclast development, and that RANK is necessary for the formation of osteolytic bone metastasis. Work from my group reveals an alternate arm of the RANK/RANKL pathway controlled by the NF-kappaB inducing kinase (NIK). Although NIK deficient mice exhibit normal osteoclast number, bone architecture and bone development, they fail to develop an osteoclastogenic response when injected with RANKL or PTH, which acts by upregulating RANKL. Moreover, osteoclast precursors from NIK-/- mice fail to develop osteoclasts in response to RANKL, in vitro. In contrast however, progenitors from NIK-/- mice can form osteoclasts, in vitro, when presented with TNFalpha and/or TGFbeta. The broad objectives of this study are to define the NIK dependent path to osteoclast differentiation, and to determine if proteins involved in this pathway (including NIK) are relevant therapeutic targets for bone metastasis. We hypothesize that: 1. Networks of genes controlled by RANKL during osteoclastogenesis are perturbed in NIK-/- cultures, and normalized by TGFbeta/TNFalpha treatment. 2. NIK-/- mice are protected from osteolytic bone metastases. Our specific aims are therefore to: 1. Use gene expression profiling to define networks of genes controlled by RANKL during osteoclastogenesis that are perturbed in NIK-/- cultures, and restored by TGFbeta/TNFalpha treatment. 2. Determine whether or not NIK-/- mice are protected from bone lesions in multiple forms of osteolytic bone metastasis.