Novel Ig-like receptor that regulates osteoclastogenesis

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。骨骼也是维持体内矿物质平衡的场所，也是造血的主要场所。骨稳态是由成骨细胞和破骨细胞的平衡作用维持的。破骨细胞吸收骨，来源于造血前体细胞。破骨细胞的形成和活化受到成骨细胞的严格调控，成骨细胞提供了至少两种破骨细胞生成的必需因子：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发生。我们最近克隆了一种新的细胞表面受体，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的表达仅限于前期和成熟破骨细胞。OSCAR表达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，在成骨细胞共培养中加入一种可溶性的OSCAR可抑制骨髓前体细胞形成破骨细胞。这些结果强烈提示OSCAR是成骨细胞诱导的破骨细胞分化的重要调节因子。LAC中的基因产生免疫球蛋白（lg）样表面受体，并在先天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发生调控的第一个例子。因此，我们建议通过以下具体目标来扩展这些破骨细胞分化过程中OSCAR的分子研究：(1)识别和表征OSCAR的配体（OSCAR- l），(2)确定OSCAR在破骨细胞分化过程中的表达是如何调节的，(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深入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，从而有助于在骨质疏松症和其他骨骼疾病的治疗和预防方面取得进展。

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.