MECHANISMS OF ACTION OF HUMAN BONE RESORPTIVE CYTOKINES

拟议研究的目的是阐明 骨吸收作用的分子机制 白介素1α、白介素1β等细胞因子与肿瘤 坏死因子、淋巴毒素、转化生长因子α 和转化生长因子β。拟议的研究将 描述这些细胞因子对第二信使的影响 三种骨骼系统中的通路：完整的胎鼠长骨 器官培养、分离的成骨细胞和分离的破骨细胞。这个 白介素1与升高环磷酸腺苷药物的相互作用 将进行完整的骨骼检查。反倾销的效果 在分离的成骨细胞中细胞因子对环磷酸腺苷途径的影响 用放射免疫法测定cAMP。效应 关于磷脂酰肌醇途径的研究将用高效液相色谱法测定 放射性标记肌醇磷酸盐的分离。的影响 吸收细胞因子或钙第二信使途径将 通过测量细胞内游离钙来检查 钙敏感荧光染料Fura-2。分离的破骨细胞 将在博伊德/钱伯斯系统中进行检查。这项研究 还将检查已知的改变第二种 信使通道。最终的目标是获得一个完整的 骨吸收药剂的作用模型。Boine Resoration是 某些慢性炎症性疾病的显著特征 包括牙周病、关节炎和骨髓炎。骨 吸收、溶骨性损害和低脱钙血症也很常见 发生在癌症中。拟议的研究对于一个 了解骨病的发病机制和治疗方法。

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.