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）： 多发性骨髓瘤（MM）生长并攻击骨骼，引起疼痛和骨相关的病理，如骨折，以及导致死亡。肿瘤和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，骨髓瘤骨病（MBD）在很大程度上仍然无法治愈。我们想知道是否只有骨骼产生的因子对骨髓瘤细胞有特异性作用。MM细胞，实验室细胞系和患者，表达激素成纤维细胞生长因子（FGF）-23的受体，这是由骨细胞，骨中丰富的细胞。在新诊断的患者中，MM中的完整血清FGF 23比对照高3倍。重组FGF 23在24小时时在2个MM细胞系中使乙酰肝素酶mRNA增加5- 18倍。乙酰肝素酶是一种分泌酶，可促进肿瘤在骨中的归巢和生长，是MM预后不良的标志物。它通过因子RANK配体增加骨破坏并抑制骨形成，从骨基质释放生长因子并修饰MM蛋白多配体聚糖-1。我们提出了一种新的骨髓瘤骨病恶性循环：A）MM细胞刺激骨细胞分泌FGF 23; B）FGF 23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、Dkk 1、骨质溶解和肿瘤生长; D）乙酰肝素酶增加骨中的肝细胞生长因子（HGF），这额外刺激MM细胞; E）FGF 23可以增强MM对骨的粘附。两位研究者联合收割机结合了对癌症的广泛个人兴趣：骨分子相互作用（JMC）和临床骨髓瘤（AS）的生物学，以及对骨髓瘤骨病的病因学和改进治疗的共同兴趣。我们提出四个具体目标：一曰：确定MM增加FGF 23的细胞途径，包括检测MM细胞产生的已知因子是否调节FGF 23的产生，或者是否受乙酰肝素酶、HGF或批准的MM治疗药物硼替佐米的调节。第二章：确定MM患者中循环FGF 23的作用，询问MM患者中FGF 23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FGF 23的骨释放。3：确定MBD中FGF 23增加的乙酰肝素酶的重要性。4.确定控制骨微环境中乙酰肝素酶表达的分子机制。该项目使用了一种新的骨髓瘤实验模型：骨相互作用。在EVOCA（离体器官培养试验）中，人MM细胞在小鼠骨上培养，这支持细胞系和患者样本的生长（这显著增加了骨中的FGF 23）。我们将使MM细胞系具有驱动分泌型端粒酶的启动子，以分析肿瘤：骨微环境中基因活性随时间的变化。避免了用活体动物进行实验，降低了成本，提高了效率，沿着消除了动物的痛苦。EVOCA使Aim 2的新研究能够使用原始样本来测试个体患者中MBD中FGF 23：乙酰肝素酶恶性循环的重要性。FGF 23和乙酰肝素酶的抑制剂正在临床试验中。我们的研究将指导其在骨髓瘤骨病和其他癌症骨转移治疗中的未来应用。