B Cell OPG Production in Bone Homeostasis

骨稳态中 B 细胞 OPG 的产生

基本信息

批准号：
7300434
负责人：
Mervyn Neale Weitzmann
金额：
$ 16.45万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-21 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7300434
关键词：
Abbreviations Ablation Accounting Adult Aging Automobile Driving B-Lymphocytes Base Pairing Bone Density Bone Marrow Bone Resorption Bone remodeling C-terminal CD40 Antigens CD40 Ligand Cells Chronic Collagen Complex Condition Core Facility Data Embryo Estrogens Generations Glucocorticoids HIV Infections Homeostasis In Vitro Interleukins Investigation Knock-out Knockout Mice Life Ligands Lymphocyte Macrophage Colony-Stimulating Factor Mature B-Lymphocyte Mature Bone Modeling Multiple Myeloma Mus NF-kappa B Nature Nude Mice Numbers Osteoblasts Osteoclasts Outcome Phenotype Physiological Polymerase Chain Reaction Population Procedures Production Regulation Relative (related person)Reporting Rheumatoid Arthritis Risk Roentgen Rays Role Source Structure T-Lymphocyte TNF gene TNFRSF5 gene TRANCE protein Thick Thymidine Kinase Tissues Transforming Growth Factor beta Transgenic Mice Transgenic Organisms Transplantation Tumor Necrosis Factor-alpha Tumor necrosis factor receptor 11b X-Ray Computed Tomography base bone bone turnover concept density design genetic manipulation immune function in vivo indexing inhibitor/antagonist receptor stem substantia spongiosa tartrate-resistant acid phosphatase

项目摘要

DESCRIPTION (provided by applicant): An in vivo role for B cells in physiological bone turnover has never been reported. Our preliminary investigations into physiological bone turnover in B cell knock out (KO) mice demonstrate that ablation of B cells results in enhanced bone resorption leading to osteopenia. Our preliminary data suggests that the mechanism driving this osteopenia is the result of a bone marrow deficit in Osteoprotegerin (OPG), the physiological decoy receptor of Receptor Activator of NF-kB Ligand (RANKL) and a potent inhibitor of osteoclast formation. Although the major source of bone marrow OPG has generally been considered to be from osteoblasts, our preliminary data suggests that bone marrow B cells represent a considerable and previously unrecognized source of osteoprotegerin in the bone marrow microenvironment and may account for up to half of the total OPG levels in bone. Furthermore we show that mice deficient in CD40 and CD40L, and in T cells likewise suffer a deficit in bone marrow OPG, due to decreased B cell OPG production. This suggests that T cells and B cells are portent protectors of bone mass under basal conditions, through regulation of B cell OPG production. Based on this data we hypothesize that B cell derived OPG is essential for the stabilization of physiological bone mass in vivo and that under basal physiological conditions lymphocytes are critical protectors of bone mass in vivo. The Specific Aims of this R21 application are to provide an unambiguous and definitive demonstration that B cells are critical preservers of physiological bone homeostasis in vivo by virtue of their capacity to secrete copious concentrations of OPG. Specific Aim 1: The generation of a Floxed OPG transgenic mouse, and the production of conditional B cell specific, and Osteoblast specific, OPG null mice. Specific Aim 2: Characterization of the bone phenotypes of a) conditional B cell specific and b) conditional osteoblast specific, OPG KO mice.

描述（由申请人提供）：从未报道过 B 细胞在生理性骨转换中的体内作用。我们对 B 细胞敲除 (KO) 小鼠的生理性骨转换的初步研究表明，B 细胞的消融会导致骨吸收增强，从而导致骨质减少。我们的初步数据表明，导致这种骨质减少的机制是骨髓中骨保护素 (OPG) 缺乏的结果，骨保护素是 NF-kB 配体受体激活剂 (RANKL) 的生理诱饵受体，也是破骨细胞形成的有效抑制剂。虽然骨髓 OPG 的主要来源通常被认为来自成骨细胞，但我们的初步数据表明，骨髓 B 细胞代表了骨髓微环境中相当大且以前未被认识的骨保护素来源，并且可能占总数的一半骨中的 OPG 水平。此外，我们发现缺乏 CD40 和 CD40L 以及 T 细胞的小鼠同样会因 B 细胞 OPG 产生减少而遭受骨髓 OPG 缺陷。这表明 T 细胞和 B 细胞通过调节 B 细胞 OPG 的产生，在基础条件下是骨量的重要保护者。基于这些数据，我们假设 B 细胞衍生的 OPG 对于体内生理骨量的稳定至关重要，并且在基础生理条件下，淋巴细胞是体内骨量的关键保护者。该 R21 应用的具体目标是提供明确且明确的证据，证明 B 细胞凭借其分泌大量 OPG 的能力，是体内生理性骨稳态的关键维护者。具体目标 1：产生 Floxed OPG 转基因小鼠，以及产生条件 B 细胞特异性和成骨细胞特异性 OPG 缺失小鼠。具体目标 2：表征 a) 条件性 B 细胞特异性和 b) 条件性成骨细胞特异性 OPG KO 小鼠的骨表型。