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。这些转移瘤通过增加破骨细胞的活性和分化而导致过度的骨吸收。最近的工作表明，RANKL/RANK通路对破骨细胞的发育至关重要，RANKL/RANK通路是溶骨性骨转移形成所必需的。我的研究小组的工作揭示了RANK/RANKL通路的另一个臂，由核因子-kappaB诱导激酶(NIK)控制。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，它们无法产生破骨反应，PTH通过上调RANKL的作用发挥作用。此外，来自Nik-/-小鼠的破骨细胞前体在体外不能产生对RANKL反应的破骨细胞。然而，与之相反，来自Nik-/-小鼠的祖细胞可以在体外形成破骨细胞，当给予TNFpha和/或TGFbeta时。本研究的主要目的是明确NIK依赖的破骨细胞分化途径，并确定参与该途径的蛋白(包括NIK)是否是骨转移的相关治疗靶点。我们假设： 1.破骨细胞形成过程中受RANKL调控的基因网络在Nik-/-培养中受到干扰，并被TGFbeta/TNFpha处理正常化。 2.NiK-/-小鼠对溶骨性骨转移有保护作用。 因此，我们的具体目标是： 1.使用基因表达谱来确定在破骨细胞形成过程中受RANKL控制的基因网络，这些基因在Nik-/-培养中受到干扰，并通过TGFbeta/TNFpha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损伤的保护。

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.