TGF-Beta Bone Fragility at the Tumor-Bone Interface in Myeloma

描述(由申请人提供)： 项目摘要/摘要拉曼光谱与显微CT解剖评估、数字Faxitron和组织形态计量学相结合，正在彻底改变评估骨骼特性和结构的方法。它们使询问骨骼中特定部位的材料成分成为可能，从而提供有关骨骼质量和脆性原因的独特信息。在这项应用中，我们希望应用这些技术(我们在Vanderbilt工程学院可用)在一个成熟的骨髓瘤临床前模型中检查骨髓瘤对骨的影响，并确定有效的抗转化生长因子-β配体的单抗对骨的这些功能特性的影响。采取这种做法有几个原因。骨髓瘤是一种疾病，其特征是对骨骼造成灾难性影响，导致顽固性疼痛和骨折易感性，表明骨骼脆性显著增加。这在退伍军人中也相对常见。我们计划研究转化生长因子-β在骨髓瘤的骨疾病中的作用，因为最近的两个观察结果--第一，转化生长因子-β已经在遗传的小鼠模型中被证明具有意想不到的特定的骨质量影响，已经被拉曼光谱证实与压缩阻力的降低(Balooch等人，2005年)，第二，最近对转化生长因子-β信号的小分子抑制剂的体外观察表明，抑制成骨细胞中的转化生长因子-β信号可以促进成骨细胞的分化，减少骨髓瘤肿瘤的负担(松本和阿贝，2006年)。我们的假设是，在骨髓瘤中，骨髓瘤细胞微环境中过量的转化生长因子-β会损害成骨细胞分化和骨质量，这种成骨细胞分化的损害间接促进了肿瘤的生长，以及(B)直接促进了肿瘤的生长。这一假设将使用下面指出的方法进行检验。我们的目标是确定(1)抗转化生长因子-β治疗是否影响骨质量并减轻骨髓瘤-骨界面的肿瘤负担，(2)抗转化生长因子-β治疗的效果是否与其他治疗方法相结合有效，以及(3)骨髓瘤中转化生长因子-β信号受损的影响是由骨髓瘤细胞介导的，还是由宿主细胞通过使用骨髓微环境中特定细胞中条件敲除转化生长因子-β信号的遗传鼠来调节的。这些临床前研究应该为骨髓瘤骨病患者的II期临床研究的设计提供指导，以确定抗转化生长因子-β方法的有效性。 公共卫生相关性： 叙述(相关性)对退伍军人医疗保健的潜在影响：我们将重点放在骨髓瘤上，因为它是退伍军人中一种重要的恶性肿瘤。这在中年及以上的男性中最为常见，在非裔美国人中的发病率是后者的两倍。在退伍军人群体中，这两个群体的比例过高。

DESCRIPTION (provided by applicant): Project Summary/Abstract Raman spectroscopy used in combination with anatomic assessment by microCT, digital Faxitron and histomorphometry are revolutionizing the ways in which bone properties and structure can be assessed. They make it possible to interrogate the material composition at specific sites in bone, and thus give unique information on bone quality and reasons for fragility.. In this application, we wish to apply these technologies (available to us in the School of Engineering at Vanderbilt) to examine the effects of myeloma on bone in a well-established preclinical model of myeloma, and to determine the effects of an effective monoclonal antibody to TGF-beta ligands on these functional properties of bone. There are several reasons for this approach. Myeloma is a disease characterized by catastrophic effects on the skeleton resulting in intractable pain and susceptibility to fracture, indicating a marked increase in bone fragility. It is also relatively common in veterans. We plan to study the role of TGF-beta in the bone disease of myeloma because of two recent observations - firstly, TGF-beta has been shown in genetic mouse models to have unexpected specific effects on bone quality that have been demonstrated by Raman spectroscopy associated with decreased resistance to a compression force (Balooch et al., 2005), and secondly, recent in vitro observations with small molecule inhibitors of TGF-beta signaling have suggested that inhibiting TGF-beta signaling in osteoblasts causes enhanced osteoblast differentiation and reduction in myeloma tumor burden (Matsumoto and Abe, 2006). Our hypothesis is that in myeloma, excess TGF-beta in the bone-myeloma cell microenvironment (a) impairs osteoblast differentiation and bone quality, and this impairment in osteoblast differentiation enhances tumor growth indirectly, and (b) enhances tumor growth directly. This hypothesis will be tested using the approaches indicated below. Our goal is to determine (1) if anti-TGF-beta therapy influences bone quality and reduces tumor burden at the myeloma - bone interface, (2) if the effects of anti-TGF-beta therapy are effective in combination with other therapeutic approaches in myeloma, and (3) if the effects of impaired TGF-beta signaling in myeloma are mediated by myeloma cells, or by host cells by the use of genetic mice with conditional knockout of TGF-beta signaling in specific cells in the bone marrow microenvironment. These preclinical studies should provide a guide for the design of phase II clinical studies in patients with myeloma bone disease to determine the efficacy of anti- TGF-beta approaches. PUBLIC HEALTH RELEVANCE: Narrative (Relevance) Potential Impact on Veterans Health Care: We are focusing on myeloma because it is an important malignancy in the Veteran population. It is most common in males of middle age and beyond, and twice as common in African-Americans. These are two groups over-represented in the Veteran population.