Role of Osteocytes in Myeloma Bone Disease

骨细胞在骨髓瘤骨病中的作用

• 批准号: 8736266
• 负责人: JOHN M CHIRGWIN
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8736266
• 关键词: Adhesions; Affect; Affinity; African American; Age; Animals; Automobile Driving; Binding; Biological Assay; Biology; Bone Diseases; Bone Matrix; Bone Pain; Bone Resorption; Bone neoplasms; Bortezomib; Breast; Calvaria; Cell Culture Techniques; Cell Line; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Data; Diagnosis; Endocrine; Enzymes; Etiology; Experimental Models; Fibroblast Growth Factor Receptors; Fracture; Future; Gene Targeting; Genes; Genetic Transcription; Growth; Growth Factor; Hepatocyte Growth Factor; Homing; Hormone Receptor; Hormones; Human; Incidence; Individual; Laboratories; Life; Luciferases; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Mediator of activation protein; Messenger RNA; Metastatic Neoplasm to the Bone; Molecular; Morbidity - disease rate; Multiple Myeloma; Mus; Myeloma Proteins; Newly Diagnosed; Organ Culture Techniques; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteolysis; Osteolytic; Pain; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma Cells; Population; Production; Prostate; Proteasome Inhibitor; Recombinant Fibroblast Growth Factor; Regulation; Research Personnel; Role; Sampling; Serum; Skeleton; Source; TNFSF11 gene; TRANCE protein; Testing; Time; Treatment Cost; Work; animal pain; base; bone; cancer type; cell type; cost; fibroblast growth factor 23; heparanase; improved; inhibitor/antagonist; interest; mortality; mouse model; outcome forecast; patient population; promoter; public health relevance; receptor; research study; response; syndecan; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Project Summary Multiple myeloma (MM) grows in and attacks the skeleton, causing pain and bone-related pathologies, such as fracture, as well as contributing to death. Many interactions between the tumor and the bone microenvironment are understood, but none involves pathways unique to bone, and myeloma bone disease (MBD) remains largely incurable. We asked whether factors made only by bone acted specifically on myeloma cells. MM cells, both laboratory cell lines and from patients, expressed the receptor for the hormone fibroblast growth factor (FGF)-23, which is made by osteocytes, abundant cells in bone. In newly diagnosed patients, intact serum FGF23 was 3X higher in MM than in controls. Recombinant FGF23 increased heparanase mRNA 5-18x in 2 MM cell lines at 24hrs. Heparanase is a secreted enzyme that enhances tumor homing and growth in bone and is a marker of poor MM prognosis. It increases bone destruction via the factor RANK ligand and suppresses bone formation, releases growth factors from bone matrix and modifies the MM protein syndecan-1. We propose a new vicious cycle of myeloma bone disease: A) MM cells stimulate osteocytes to secrete FGF23; B) FGF23 increases heparanase expression by MM cells; C) Heparanase alters the bone microenvironment and increases RANK ligand, Dkk1, osteolysis & tumor growth; D) Heparanase increases hepatocyte growth factor (HGF) in bone, which additionally stimulates MM cells; E) FGF23 may enhance MM adhesion to bone. The two Investigators combine extensive individual interests in cancer:bone molecular interactions (JMC) and the biology of clinical myeloma (AS) with a shared interest in the etiology and improved treatment of myeloma bone disease. We propose Four Specific Aims: 1: Determine the cellular pathways by which MM increases FGF23, including testing if known factors made by MM cells regulate FGF23 production, or if it is regulated by heparanase, HGF or the approved MM treatment bortezomib. 2: Determine the role of circulating FGF23 in MM patients, asking if FGF23 & heparanase concentrations are correlated in MM patients and testing if MM cells from patients increase bone release of FGF23. 3: Determine the importance of FGF23-increased heparanase in MBD. 4. Determine molecular mechanisms that control heparanase expression in the bone microenvironment. The project uses a new experimental model of myeloma:bone interactions. In EVOCA (ex vivo organ culture assay), human MM cells are cultured on mouse bone, which supports growth of cell lines and patient samples (which dramatically increase FGF23 in bone). We will make MM cell lines with promoters driving secreted luciferases to analyze changes in gene activity over time in the tumor:bone microenvironment. Experiments with live animal are avoided, lowering costs & increasing efficiency, along with elimination of animal pain & suffering. EVOCA enables new studies in Aim 2 with primary samples to test the importance of the FGF23:heparanase vicious cycle in MBD in individual patients. Inhibitors of FGF23 & heparanase are in clinical trials. Our studies will guide their future application to the treatmentof myeloma bone disease and other cancer bone metastases.

描述（由申请人提供）： 项目摘要 多发性骨髓瘤 (MM) 在骨骼中生长并侵袭骨骼，导致疼痛和与骨骼相关的病变，例如骨折，并导致死亡。肿瘤与骨微环境之间的许多相互作用已被了解，但没有一个涉及骨特有的途径，并且骨髓瘤骨病（MBD）在很大程度上仍然无法治愈。我们询问仅由骨骼产生的因子是否专门作用于骨髓瘤细胞。 MM 细胞（包括实验室细胞系和患者细胞）表达激素成纤维细胞生长因子 (FGF)-23 的受体，该受体由骨细胞（骨中丰富的细胞）产生。在新诊断的 MM 患者中，完整血清 FGF23 比对照组高 3 倍。 24 小时后，重组 FGF23 将 2 个 MM 细胞系中的乙酰肝素酶 mRNA 增加了 5-18 倍。乙酰肝素酶是一种分泌酶，可增强肿瘤在骨中的归巢和生长，是 MM 预后不良的标志。它通过因子 RANK 配体增加骨破坏并抑制骨形成，从骨基质中释放生长因子并修饰 MM 蛋白 syndecan-1。我们提出了骨髓瘤骨病的新恶性循环：A）MM细胞刺激骨细胞分泌FGF23； B) FGF23 增加 MM 细胞的乙酰肝素酶表达； C) 乙酰肝素酶改变骨微环境并增加 RANK 配体、Dkk1、骨质溶解和肿瘤生长； D) 乙酰肝素酶会增加骨骼中的肝细胞生长因子 (HGF)，从而进一步刺激 MM 细胞； E) FGF23 可以增强 MM 对骨的粘附。两位研究人员将个人对癌症：骨分子相互作用 (JMC) 和临床骨髓瘤 (AS) 生物学的广泛兴趣与对骨髓瘤骨病的病因学和改进治疗的共同兴趣结合起来。我们提出四个具体目标： 1：确定 MM 增加 FGF23 的细胞途径，包括测试 MM 细胞产生的已知因子是否调节 FGF23 的产生，或者它是否受到乙酰肝素酶、HGF 或已批准的 MM 治疗硼替佐米的调节。图2：确定循环FGF23在MM患者中的作用，询问MM患者中的FGF23和乙酰肝素酶浓度是否相关，并测试来自患者的MM细胞是否增加FGF23的骨释放。图 3：确定 FGF23 增加的乙酰肝素酶在 MBD 中的重要性。 4. 确定控制骨微环境中乙酰肝素酶表达的分子机制。该项目使用骨髓瘤：骨相互作用的新实验模型。在 EVOCA（离体器官培养测定）中，人类 MM 细胞在小鼠骨骼上培养，支持细胞系和患者样本的生长（这会显着增加骨骼中的 FGF23）。我们将制作带有驱动分泌荧光素酶的启动子的 MM 细胞系，以分析肿瘤：骨微环境中基因活性随时间的变化。避免使用活体动物进行实验，从而降低成本并提高效率，同时消除动物的疼痛和痛苦。 EVOCA 能够利用原始样本进行 Aim 2 中的新研究，以测试 FGF23：乙酰肝素酶恶性循环在个体患者 MBD 中的重要性。 FGF23 和乙酰肝素酶抑制剂正在进行临床试验。我们的研究将指导它们未来在治疗骨髓瘤骨病和其他癌症骨转移中的应用。