TUMOR CELL-DERIVED OSTEOCLAST GROWTH FACTOR

肿瘤细胞衍生的破骨细胞生长因子

• 批准号: 3161264
• 负责人: MINAKO Y LEE
• 金额: $ 18.52万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 1994-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3161264
• 关键词: bone marrow; calcitonin; hypercalcemia; laboratory mouse; mixed tissue /cell culture; molecular cloning; nonhuman therapy evaluation; osteoclast activating factor; osteoclasts; osteopetrosis; pathologic bone resorption; physiologic bone resorption; protein purification; protein structure function; recombinant DNA; scanning electron microscopy; tissue /cell culture

Despite its important role in the maintenance of healthy bone tissue, the osteoclast is still a poorly understood cell. The long term objective of this proposal is to increase our understanding of the regulation and development of osteoclasts. Our recent studies have shown that a well characterized hypercalcemia-inducing murine mammary tumor, CE mammary carcinoma, produces a new growth factor which stimulates bone marrow progenitors that give rise to cells with osteoclast characteristics. It is our hypothesis that this factor is the growth regulator of the osteoclast, "osteoclast-colony stimulating factor" (O-CSF), and is responsible for excessive bone resorption induced by this tumor. This hypothesis will be tested by further characterization of the responding cells in the bone marrow and definitive biochemical and functional studies of the molecule. The cells responding to this factor will be investigated by co-cultivation with bone pieces to demonstrate bone excavation. The osteoclast colony stimulating factor will be isolated and purified by biochemical protein separation procedures, followed by amino acid sequencing and cloning of cDNA; the recombinant molecule will be obtained by molecular cloning techniques. The physiological role of the growth factor for bone resorption and induction of hypercalcemia will be investigated by injecting the recombinant molecule into normal and osteopetrotic mice, by performing histochemical and morphometric analysis of bones and by analysis of serum calcium. Our approach to the studies of osteoclasts by clonal analysis of bone marrow progenitors will bring a new insight into the molecular regulation of osteoclasts. Certain tumors are abundant sources for growth factors and are known to influence functions of the host, such as severe hypercalcemia. Molecular characterization of the O-CSF in murine system will allow us to extend the studies of such a molecule in human in the future and will contribute to the understanding of various bone disorders, such as osteoporosis and osteopetrosis, as well as for humoral hypercalcemia of malignancy, a serious complication associated with certain cancer patients.

尽管它在维持健康的骨组织方面发挥着重要作用，但 破骨细胞仍然是一个知之甚少的细胞。的长期目标是 这项建议是为了增加我们对该法规和 破骨细胞的发育。我们最近的研究表明，一口井 以高钙诱导的小鼠乳腺肿瘤为特征 癌症会产生一种新的生长因子，刺激骨髓 产生具有破骨细胞特征的细胞的祖细胞。它是 我们假设这个因子是破骨细胞的生长调节器， “破骨细胞集落刺激因子”(O-CSF)，并负责 这种肿瘤引起的过度骨吸收。这一假设将是 通过对骨骼中的反应细胞的进一步特征进行测试 骨髓和明确的生物化学和分子功能研究。 对该因子有反应的细胞将通过共培养进行研究。 用骨头碎片来展示骨头的挖掘。破骨细胞集落 利用生化蛋白分离纯化刺激因子 分离程序，随后进行氨基酸测序和克隆 通过分子克隆获得重组分子。 技巧。骨生长因子的生理作用 通过注射研究高钙血症的吸收和诱导 将重组分子导入正常和骨质疏松症小鼠，通过 骨的组织化学和形态计量学分析及血清分析 钙。我们通过克隆分析研究破骨细胞的方法 骨髓祖细胞将带来对分子的新见解 破骨细胞的调控。某些肿瘤是丰富的生长来源。 影响寄主功能的因素，如严重的 高钙血症。O-CSF在小鼠体内的分子生物学特性 将使我们能够扩展对这种分子在人类中的研究 未来，将有助于理解各种骨骼疾病， 如骨质疏松症和骨化症，以及体液 恶性高血钙症，与某些严重并发症相关 癌症患者。