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

骨髓瘤肿瘤-骨界面处的 TGF-β 骨脆性

• 批准号: 7687857
• 负责人: GREGORY R MUNDY
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687857
• 关键词: Address; African American; Anatomy; Antibodies; Biomechanics; Bone Diseases; Bone Marrow; Bone Resorption; Bone neoplasms; Bortezomib; Cells; Characteristics; Clinical Research; Data; Disease; Disease model; Engineering; Environment; Event; Fracture; Genetic; Goals; Growth; Health; Healthcare; Impairment; In Vitro; Institutes; Intractable Pain; Knock-out; Knockout Mice; Lead; Ligands; Lytic Metastatic Lesion; Malignant Neoplasms; Maps; Marrow; Measurement; Measures; Mediating; Minerals; Modeling; Monoclonal Antibodies; Multiple Myeloma; Mus; Mutation; Osteoblasts; Osteolysis; Patients; Pharmacotherapy; Phase; Phosphotransferases; Population; Pre-Clinical Model; Predisposition; Property; Proteasome Inhibitor; Protocols documentation; Quality of life; Raman Spectrum Analysis; Resistance; Role; Schools; Serum; Signal Transduction; Site; Skeleton; Staging; Stromal Cells; Structure; Tail; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Tumor Burden; Veins; Veterans; Zoledronic Acid; abstracting; base; bisphosphonate; bone; bone geometry; bone growth factor; bone quality; bone toughness; density; design; digital; effective therapy; improved; inhibitor/antagonist; male; middle age; mouse model; neoplastic cell; neutralizing monoclonal antibodies; normal aging; optical imaging; osteoblast differentiation; preclinical study; receptor; research study; skeletal; small molecule; submicron; tumor growth

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.

描述（由申请人提供）： 项目摘要/摘要拉曼光谱与microCT、数字化Faxitron和组织形态计量学的解剖评估相结合，正在彻底改变骨特性和结构的评估方式。它们可以询问骨中特定部位的材料成分，从而提供有关骨质量和脆性原因的独特信息。在本申请中，我们希望应用这些技术（可在范德比尔特工程学院获得），以在完善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TGF-β配体单克隆抗体对骨的这些功能特性的影响。采取这种做法有几个原因。骨髓瘤是一种以骨骼灾难性影响为特征的疾病，导致顽固性疼痛和骨折易感性，表明骨脆性显著增加。这在退伍军人中也相对常见。我们计划研究TGF-β在骨髓瘤的骨疾病中的作用，因为最近的两个观察结果-首先，TGF-β在遗传小鼠模型中显示出对骨质量具有意想不到的特异性作用，这已经通过与对压缩力的抵抗力降低相关的拉曼光谱证明（Balooch et al.，2005），其次，最近用TGF-β信号传导的小分子抑制剂进行的体外观察表明，抑制成骨细胞中的TGF-β信号传导导致成骨细胞分化增强和骨髓瘤肿瘤负荷降低（松本和Abe，2006）。我们的假设是，在骨髓瘤中，骨-骨髓瘤细胞微环境中过量的TGF-β（a）损害成骨细胞分化和骨质量，成骨细胞分化的这种损害间接促进肿瘤生长，和（B）直接促进肿瘤生长。这一假设将使用下述方法进行检验。我们的目标是确定（1）抗TGF-β治疗是否影响骨质量并降低骨髓瘤-骨界面处的肿瘤负荷，（2）抗TGF-β治疗的效果与骨髓瘤中的其他治疗方法组合是否有效，以及（3）骨髓瘤中受损的TGF-β信号传导的效果是否由骨髓瘤细胞介导，或通过使用在骨髓微环境中的特定细胞中具有条件性敲除TGF-β信号传导的遗传小鼠通过宿主细胞。这些临床前研究应该为骨髓瘤骨病患者的II期临床研究设计提供指导，以确定抗TGF-β方法的疗效。 公共卫生关系： 叙述（相关性）对退伍军人医疗保健的潜在影响：我们关注骨髓瘤，因为它是退伍军人人群中的一种重要恶性肿瘤。它在中年及以上的男性中最常见，在非洲裔美国人中是两倍。这两个群体在退伍军人中的比例过高。