BONE RESORPTION--IMMUNE AND ENDOCRINE RELATIONSHIPS

骨吸收——免疫和内分泌的关系

• 批准号: 2390502
• 负责人: STEVEN N. POPOFF
• 金额: $ 17.18万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-03-15 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2390502
• 关键词: B lymphocyte; T lymphocyte; binding proteins; flow cytometry; histochemistry /cytochemistry; immunoregulation; injection /infusion; laboratory rat; leukocyte activation /transformation; macrophage activating factor; messenger RNA; mutant; natural killer cells; northern blottings; nucleic acid sequence; osteoclasts; osteocytes; osteopetrosis; pathologic bone resorption; polymerase chain reaction; tissue /cell culture; vitamin D; vitamin metabolism

The mammalian osteopetroses are a diverse group of inherited bone disorders characterized by a generalized increase in skeletal mass resulting from reduced osteoclastic bone resorption. Various abnormalities in cellular and humoral immunity have been identified in osteopetrotic animals and children. Some osteopetrotic animal mutations represent unique in vivo models to explore interactions between the immune and skeletal systems. Specifically, we have been studying possible relationships between coexisting defects in immune cell and osteoclast functions in the osteopetrotic (op) rat. This laboratory recently demonstrated a defect in inflammation-primed macrophage activation resulting from the inability to convert serum vitamin D binding protein .(DBP) to a potent macrophage activating factor (DBP-MAF). This defect is due to the absence of an inducible beta-galactosidase isoenzyme associated with B cell membranes in op mutants. Furthermore, treatment of op mutants with exogenous DBP-MAF resulted in osteoclast activation. Collectively, these results support the hypothesis that DBP-MAF plays an important role in the pathogenesis of osteoclast hypofunction in some forms of osteopetrosis. Studies proposed in this application will test this hypothesis. B cells from normal rats will be transplanted into op mutants in an attempt to correct the B cell defect and cure osteopetrosis by restoring normal osteoclast function. Op mutants and normal rats will be treated with exogenous DBP-MAF at various doses and for different periods of time to; 1) determine if the excess skeletal mass can be completely resorbed in op mutants, and 2) test the effects of this novel factor on osteoclast function and skeletal modeling in normal rats. To gain a better understanding of the mechanism(s) of action of DBP-MAF proposed experiments will; l) examine structural requirements necessary for MAF activity, and 2) evaluate DBP-MAF binding to various immune cells and bone cells in situ. Finally, the powerful mRNA-differential display technique will be used to identify genes selectively expressed in bone from normal or osteopetrotic rats. These studies are expected to provide new clinical applications concerning the therapeutic management of osteopetrotic children and to broader aspects of skeletal pathology including inflammation-mediated osteopenias. As a direct application, exogenous DBP-MAF could be used to treat osteopetrotic children in an attempt to activate osteoclasts and reduce skeletal mass. Based on its potent osteoclast activating property, DBP-MAF may play a key role in mediating the bone loss often associated with chronic inflammatory diseases, such as periodontal disease, osteoarthritis and rheumatoid arthritis. Future studies aimed at developing methods to "block" its osteolytic effect could be used therapeutically to inhibit inflammation- mediated bone loss.

哺乳动物的骨质术是一组遗传的骨骼 以骨骼质量增加的特征的疾病 由骨质碎片骨吸收减少而导致。各种异常 在骨质术中已经鉴定出细胞和体液免疫 动物和儿童。某些骨质造成动物突变代表独特 体内模型以探索免疫和骨骼之间的相互作用 系统。具体来说，我们一直在研究可能的关系 在免疫细胞中共存的缺陷和破骨细胞功能之间 骨质原子（OP）大鼠。该实验室最近证明了 炎症引发的巨噬细胞激活是由于无法 将血清维生素D结合蛋白转换为有效的巨噬细胞 激活因子（DBP-MAF）。该缺陷是由于没有 与B细胞膜相关的诱导β-半乳糖苷酶同工酶同工酶 OP突变体。此外，用外源DBP-MAF处理OP突变体 导致破骨细胞激活。总的来说，这些结果支持 DBP-MAF在 某些形式的骨质疏松症中的骨细胞功能低下。研究提出 在此应用中，将检验该假设。来自正常大鼠的B细胞 将被移植到OP突变体中，以试图纠正B细胞 通过恢复正常的破骨细胞功能，缺陷和治愈骨质膜病。 OP 突变体和正常大鼠将在各种情况下用外源DBP-MAF处理 剂量和不同的时间； 1）确定是否过多 骨骼质量可以在OP突变体中完全渗透，2）测试 这种新因素对破骨细胞功能和骨骼建模的影响 在正常大鼠中。为了更好地了解 DBP-MAF提出的实验的作用； l）检查结构 MAF活动所需的要求，2）评估DBP-MAF绑定 原位到各种免疫细胞和骨细胞。最后，有权势 mRNA差异显示技术将用于识别基因 从正常或骨质术大鼠中有选择地表达在骨骼中。这些 预计研究将提供有关有关的新临床应用 骨质骨儿童的治疗管理和更广泛的方面 骨骼病理学，包括炎症介导的骨质减少症。作为 直接应用，外源DBP-MAF可用于治疗骨质术 儿童试图激活破骨细胞并减少骨骼质量。 DBP-MAF基于其有效的破骨细胞激活属性，可能会播放钥匙 通常与慢性炎症有关的骨骼流失的作用 疾病，例如牙周疾病，骨关节炎和类风湿病 关节炎。未来的研究旨在开发“阻止”其的方法 溶性作用可以治疗用来抑制炎症 - 介导的骨质流失。