MECHANISMS OF ACTION OF HUMAN BONE RESORPTIVE CYTOKINES

人骨吸收细胞因子的作用机制

• 批准号: 3221043
• 负责人: Floyd E Dewhirst
• 金额: $ 24.52万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1992-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3221043
• 关键词: arthritis; calcium metabolism; cell bank /registry; cyclic AMP; cytokine; cytoplasm; dental research; diacylglycerols; embryo /fetus; high performance liquid chromatography; hypercalcemia; inositol phosphates; interleukin 1; laboratory mouse; laboratory rat; neuropeptides; organ culture; osteoclast activating factor; osteoclasts; osteomyelitis; pathologic bone resorption; phosphatidylinositols; radioimmunoassay; radiotracer; second messengers; skeletal pharmacology; transforming growth factors; tumor necrosis factor alpha; tumor necrosis factor beta

The objective of the proposed research is to elucidate the molecular mechanisms involved in the action of bone resorptive cytokines including interleukin 1 alpha, interleukin 1 beta, tumor necrosis factor, lymphotoxin, transforming growth factor alpha and transforming growth factor beta. The proposed research will characterize the effect of these cytokines on second messenger pathways in three bone systems: intact fetal rat long bone in organ culture, isolated osteoblasts and isolated osteoclasts. The interaction of interleukin 1 with agents that elevate cyclic AMP will be examined in whole bone. The effect of resoprtive cytokines on the cyclic AMP pathway in isolated osteoblasts will be determined by measuring cAMP by radioimmunoassay. Effects on the phosphotidylinositol pathway will be determined by HPLC separation of radiolabeled inositol phosphates. The effect of resorptive cytoskines or calcium second messenger pathway will be examined by measuring cytosolic free calcium using the calcium sensitive flluorescent dye Fura-2. Isolated osteoclasts will be examined in the Boyde/Chambers system. The research will also examine pharmacologic agents known to modify second messenger pathways. The ultimate goal is to obtain an integrated model of the action of bone resorptive agents. Boine resorption is a prominent feature of certain chronic inflammatory diseases including periodontal disease, arthritis and osteomyelitis. Bone resorption, osteolytic lesions and hypdecalcemia also commonly occur in cancer. The proposed research is necessary to an understanding of the pathogenesis and treatment of bone diseases.

拟议研究的目的是阐明 骨吸收作用的分子机制 细胞因子包括白细胞介素1 α、白细胞介素1 β、肿瘤 坏死因子、光氧素、转化生长因子α 和转化生长因子β。 拟议的研究将 表征这些细胞因子对第二信使的作用， 三种骨系统中的通路： 器官培养、分离成骨细胞和分离破骨细胞。 的 白细胞介素1与升高环腺苷酸试剂的相互作用 将在整个骨骼中进行检查。 反应的影响 在分离的成骨细胞中，环AMP途径上的细胞因子将 通过放射免疫测定法测量cAMP来确定。 影响 将通过HPLC测定对磷脂酰肌醇途径的影响 分离放射性标记的肌醇磷酸。 的影响 再吸收细胞质或钙第二信使途径将 通过测量细胞溶质游离钙进行检查， 钙敏感荧光染料Fura-2。 分离破骨细胞 将在Boyde/Chambers系统中进行检查。 研究 还将检查已知可改变第二种 信使通道 最终目标是获得一个完整的 骨吸收剂作用的模型。 牛骨吸收是 某些慢性炎症性疾病的一个显著特征 包括牙周病、关节炎和骨髓炎。 骨 骨吸收、溶骨性病变和高钙血症也常见 发生在癌症中。 建议的研究是必要的， 了解骨骼疾病的发病机制和治疗方法。