Role of Microenvironmental-Derived AXII in Myeloma Bone Disease

微环境衍生的 AXII 在骨髓瘤骨病中的作用

• 批准号: 8245284
• 负责人: Garson DAVID ROODMAN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245284
• 关键词: Affect; African American; Angiogenic Factor; Annexins; Binding; Biological Assay; Bone Diseases; Bone Marrow; Bone Matrix; Bone Regeneration; Bone Resorption; Breeding; Caucasians; Caucasoid Race; Cell Adhesion Molecules; Cell Proliferation; Cell physiology; Cells; Characteristics; Conditioned Culture Media; Data; Development; Dichloromethylene Diphosphonate; Disease; Elderly; Endothelial Cells; Event; Growth; Growth Factor; Health; Human; Immunocompetent; In Vitro; Knock-out; Lead; Lytic; Malignant lymphoid neoplasm; Marrow; Mediating; Medical Research; Messenger RNA; Modeling; Multiple Myeloma; Mus; Newly Diagnosed; Osteoblasts; Osteoclasts; Patients; Plasmin; Plasminogen; Play; Pre-Clinical Model; Process; Production; Property; Protocols documentation; Quality of life; Reporting; Role; Signal Transduction; Source; Stromal Cells; Surface; System; Testing; United States; Veterans; Zoledronic Acid; angiogenesis; bisphosphonate; bone; cell type; chemokine; chemotherapy; cytokine; dimer; improved; in vivo; in vivo Model; inhibitor/antagonist; insight; migration; monomer; novel; osteoclastogenesis; receptor; skeletal; tumor; tumor growth

DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is characterized by increased angiogenesis and bone destruction, which both result in enhanced tumor growth. Blocking either tumor associated angiogenesis or bone resorption by osteoclasts (OCL) significantly impacts MM growth in preclinical models. Further, the recent Medical Research Council Myeloma IX trial, which compared zoledronic acid and clodronate, both inhibitors of OCL activity, in combination with chemotherapy in patients with newly diagnosed MM, showed that zoledronic acid treatment significantly increased survival by 5.5 months compared to the weaker bisphosphonate clodronate, and that this survival benefit was independent of skeletal-related events. Importantly, 30% of the patients in this trial did not have lytic bone disease at the start of the trial and still benefited from zoledronic acid therapy. These results suggest that blocking OCL activity may have additional inhibitory effects on tumor growth beyond effects on bone resorption. Consistent with this possibility, we recently reported that OCL are angiogenic cells both in vivo and in vitro, suggesting that OCL may contribute to the enhanced angiogenesis in MM. In support of this hypothesis, we have demonstrated that Annexin 2 (AXII) is secreted by OCL, is a growth factor for MM cells and can stimulate proliferation of human endothelial cells. These results suggest that OCL have a multiplicity of effects in myeloma that result in enhanced tumor growth and bone destruction. However, the role of OCL-derived AXII in MM is unclear. It is our hypothesis that the increased OCL activity present in MM patients increases tumor growth, both through secretion of growth factors and angiogenic factors such as AXII by OCL and release of MM growth factors from the bone matrix. Further, release of AXII from bone marrow stromal cells and OCL increases production of cytokines by MM cells that induce osteoclastogenesis, osteoblast suppression, and angiogenesis. Therefore, to test this hypothesis, we will assess the role of microenvironment-derived AXII in myeloma bone disease (MMBD) by pursuing the following specific aims: 1) Determine if modulating AXII produced in the MM microenvironment by bone marrow stromal cells and OCL impacts the capacity of MM cells to induce osteoclastogenesis, osteoblast suppression, and angiogenesis. 2) Determine if OCL-derived AXII acts as an angiogenic factor. 3) Determine the role of marrow microenvironment-derived AXII on angiogenesis, tumor growth and bone destruction in MM using our recently developed immunocompetent in vivo model of MMBD. As part of this aim, we will determine the contribution of OCL-derived AXII to these processes to test the hypothesis that OCL make multiple contributions to tumor growth, bone destruction and the increased angiogenesis characteristic of MM in vivo. Thus, In this proposal, we will determine the roles of both bone marrow stromal cell-derived and in particular OCL-derived AXII activity in MMBD and their respective roles in regulating MM cell functions including osteoblast suppression, enhanced osteoclastogenesis, and production of pro-angiogenic factors (AIM 1); determine the capacity of OCL-derived AXII's capacity to act directly as an angiogenic factor on endothelial cells (AIM 2); and determine the role of microenvironment-derived AXII (total knockout) and specifically of OCL-derived AXII (conditional knockout) in tumor growth, bone destruction and angiogenesis in vivo (AIM 3).

描述（由申请人提供）： 多发性骨髓瘤 (MM) 的特点是血管生成和骨质破坏增加，这两者都会导致肿瘤生长加快。在临床前模型中，阻断肿瘤相关的血管生成或破骨细胞 (OCL) 的骨吸收会显着影响 MM 的生长。此外，最近的医学研究委员会骨髓瘤 IX 试验比较了唑来膦酸和氯膦酸盐（两种 OCL 活性抑制剂）与新诊断 MM 患者的化疗相结合，结果表明，唑来膦酸治疗与较弱的治疗相比，显着延长了 5.5 个月的生存期双膦酸盐氯膦酸盐，并且这种生存获益与骨骼相关事件无关。重要的是，该试验中 30% 的患者在试验开始时并未患有溶骨病，但仍受益于唑来膦酸治疗。这些结果表明，阻断 OCL 活性除了对骨吸收的影响之外，还可能对肿瘤生长产生额外的抑制作用。与这种可能性一致，我们最近报道 OCL 在体内和体外都是血管生成细胞，表明 OCL 可能有助于增强 MM 的血管生成。为了支持这一假设，我们证明了膜联蛋白 2 (AXII) 由 OCL 分泌，是 MM 细胞的生长因子，可以刺激人内皮细胞的增殖。这些结果表明 OCL 对骨髓瘤具有多种作用，导致肿瘤生长增强和骨质破坏。然而，OCL 衍生的 AXII 在 MM 中的作用尚不清楚。我们的假设是，MM 患者中存在的 OCL 活性增加，通过 OCL 分泌生长因子和血管生成因子（例如 AXII）以及从骨基质中释放 MM 生长因子，从而促进肿瘤生长。此外，骨髓基质细胞和 OCL 释放 AXII 会增加 MM 细胞产生的细胞因子，从而诱导破骨细胞生成、成骨细胞抑制和血管生成。因此，为了检验这一假设，我们将通过追求以下具体目标来评估微环境衍生的 AXII 在骨髓瘤骨病 (MMBD) 中的作用：1) 确定骨髓基质细胞和 OCL 影响是否调节 MM 微环境中产生的 AXII MM细胞诱导破骨细胞生成、成骨细胞抑制和血管生成的能力。 2) 确定 OCL 衍生的 AXII 是否充当血管生成因子。 3) 使用我们最近开发的 MMBD 免疫活性体内模型确定骨髓微环境衍生的 AXII 对 MM 血管生成、肿瘤生长和骨破坏的作用。作为该目标的一部分，我们将确定 OCL 衍生的 AXII 对这些过程的贡献，以检验 OCL 对体内肿瘤生长、骨破坏和 MM 血管生成增加特征的多重贡献的假设。因此，在本提案中，我们将确定骨髓基质细胞衍生的，特别是 OCL 衍生的 AXII 活性在 MMBD 中的作用，以及它们各自在调节 MM 细胞功能中的作用，包括成骨细胞抑制、增强破骨细胞生成和前体细胞的产生。血管生成因子（AIM 1）；确定 OCL 衍生的 AXII 直接作为内皮细胞血管生成因子发挥作用的能力 (AIM 2)；并确定微环境衍生的 AXII（全敲除），特别是 OCL 衍生的 AXII（条件敲除）在体内肿瘤生长、骨质破坏和血管生成中的作用 (AIM 3)。