Novel Ig-like receptor that regulates osteoclastogenesis

调节破骨细胞生成的新型 Ig 样受体

• 批准号: 6533451
• 负责人: YONGWON CHOI
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-24 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533451
• 关键词: antibody receptor; cell differentiation; cell growth regulation; gene targeting; genetic promoter element; genetic regulatory element; genetically modified animals; intermolecular interaction; laboratory mouse; ligands; osteoclasts; physiologic bone resorption; receptor expression

DESCRIPTION (provided by applicant): Bones provide rigid support for the body, mechanical integrity of movement, and protection. Bones also serve as a site of mineral homeostasis as well as the primary site for hematopoiesis. Bone homeostasis is maintained by the balanced action of osteoblasts and osteoclasts. Osteoclasts resorb bone and are derived from hematopoietic precursor cells. The formation and activation of osteoclasts are tightly regulated by osteoblasts, which provide at least two essential factors for osteoclastogenesis, TRANCE and M-CSF. In addition, various stromal cells produce different osteotropic factors that further influence osteoblast-induced osteoclastogenesis. We have recently cloned a novel cell surface receptor, termed OSCAR (osteoclast associated receptor), which is a new member of the leukocyte receptor complex (LRC) proteins. OSCAR expression is restricted to pre- and mature osteoclasts. Expression of the ligand for OSCAR expression is restricted to osteoblasts. Our studies show that addition of a soluble form of OSCAR in co-culture with osteoblasts inhibits the formation of osteoclasts from bone marrow precursor cells in the presence of bone resorbing factors. These results strongly suggest that OSCAR is an important regulator of osteoblast-induced osteoclast differentiation. Genes in the LAC produce immunoglobulin (lg)-like surface receptors and play critical roles in the regulation of both innate and adaptive immune responses. However, OSCAR is the first example of an LRC-encoded protein that is implicated in the regulation of osteoclastogenesis. Therefore, we propose to extend these molecular studies of OSCAR during osteoclast differentiation by pursuing the following specific aims: (1) identifying and characterizing ligand(s) for OSCAR (OSCAR-L), (2) determining how OSCAR expression is regulated during osteoclast differentiation, (3) determining the role of OSCAR in vivo. The knowledge gained from these studies will provide insights into how different molecules cooperate in inducing osteoclast differentiation, and how osteoclasts and osteoblasts communicate to regulate each other's function, which, in turn, may help to make strides in the treatment and prevention of osteoporosis and other bone diseases.

描述（由申请人提供）：骨骼为身体提供刚性支撑、运动的机械完整性和保护。骨骼也是矿物质稳态的场所以及造血的主要场所。骨稳态是通过成骨细胞和破骨细胞的平衡作用来维持的。破骨细胞吸收骨并源自造血前体细胞。破骨细胞的形成和激活受到成骨细胞的严格调控，成骨细胞为破骨细胞生成提供至少两个必需因子：TRANCE和M-CSF。此外，各种基质细胞产生不同的成骨因子，进一步影响成骨细胞诱导的破骨细胞生成。我们最近克隆了一种新型细胞表面受体，称为 OSCAR（破骨细胞相关受体），它是白细胞受体复合物（LRC）蛋白的新成员。 OSCAR 表达仅限于前破骨细胞和成熟破骨细胞。 OSCAR表达的配体的表达仅限于成骨细胞。我们的研究表明，在骨吸收因子存在的情况下，在与成骨细胞共培养中添加可溶形式的 OSCAR 可抑制骨髓前体细胞形成破骨细胞。这些结果强烈表明 OSCAR 是成骨细胞诱导的破骨细胞分化的重要调节剂。 LAC 中的基因产生免疫球蛋白 (lg) 样表面受体，并在先天性和适应性免疫反应的调节中发挥关键作用。然而，OSCAR 是 LRC 编码蛋白参与破骨细胞生成调节的第一个例子。因此，我们建议通过追求以下具体目标来扩展破骨细胞分化过程中 OSCAR 的分子研究：（1）鉴定和表征 OSCAR 配体（OSCAR-L），（2）确定破骨细胞分化过程中 OSCAR 表达如何调节，（3）确定 OSCAR 在体内的作用。从这些研究中获得的知识将有助于了解不同分子如何合作诱导破骨细胞分化，以及破骨细胞和成骨细胞如何沟通以调节彼此的功能，这反过来可能有助于在骨质疏松症和其他骨疾病的治疗和预防方面取得进展。