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）的特征是血管生成和骨骼破坏增加，这两者都会导致肿瘤的生长增强。通过破骨细胞（OCL）阻断肿瘤相关的血管生成或骨吸收会显着影响临床前模型中的MM生长。 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.重要的是，该试验中有30％的患者在试验开始时没有裂解骨疾病，并且仍然受益于唑来膦酸治疗。这些结果表明，阻断OCL活性可能会对肿瘤生长产生额外的抑制作用，超出对骨吸收的影响。与这种可能性一致，我们最近报道了OCL是体内和体外的血管生成细胞，这表明OCL可能有助于MM中的血管生成增强。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在骨髓瘤中具有多种作用，从而导致肿瘤生长和骨骼破坏增强。但是，OCL衍生的AXII在MM中的作用尚不清楚。我们的假设是，通过分泌生长因子和血管生成因子，例如OCL通过OCL的分泌以及从骨基质中释放MM生长因子，从而增加了MM患者的OCL活性增加肿瘤的生长。此外，从骨髓基质细胞中释放AXII和OCL可通过诱导破骨细胞生成，成骨细胞抑制和血管生成的MM细胞增加细胞因子的产生。 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）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体内免疫能力模型，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。作为此目标的一部分，我们将确定OCL衍生的AXII对这些过程的贡献，以测试OCL对体内MM的肿瘤生长，骨骼破坏和血管生成的增加的多种贡献。因此，在此提案中，我们将确定MMBD中骨髓间基质细胞衍生，尤其是OCL衍生的AXII活性的作用，及其在调节MM细胞功能中的作用，包括成骨细胞抑制，增强的骨质现代骨质发生，并产生促骨质质发生和产生（促血管基因生成因子（AIM AIM 1）；确定OCL衍生的Axii直接作为内皮细胞的血管生成因子的能力（AIM 2）；并确定微环境衍生的AXII（总敲除），特别是OCL衍生的AXII（条件敲除）在体内肿瘤生长，骨骼破坏和血管生成中的作用（AIM 3）。