T Cells and PTH Induced Bone Loss

T 细胞和 PTH 诱导的骨丢失

• 批准号: 8544972
• 负责人: ROBERTO PACIFICI
• 金额: $ 33.24万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-24 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544972
• 关键词: Adoptive Transfer; Anabolism; Antibodies; Binding; Biology; Bone Formation Stimulation; Bone Growth; Bone Resorption; Cells; Complex; Data; Disease model; Exhibits; Genes; Grant; Hormones; Hyperparathyroidism; Infusion procedures; Knowledge; Laboratories; Lead; Ligands; Lymphocyte; Mediating; Modeling; Mus; Nature; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Parathyroid Hormone Receptor; Play; Production; Public Health; Publishing; Regimen; Reporting; Role; Signal Transduction; T-Lymphocyte; TNF gene; Transgenic Mice; base; bone; bone cell; bone loss; bone mass; cytokine; insight; new therapeutic target; novel; osteogenic; overexpression; public health relevance; receptor; response; substantia spongiosa

DESCRIPTION (provided by applicant): Continuous PTH (cPTH) treatment causes bone loss while intermittent PTH (iPTH) treatment increases bone mass, but the reasons for the differential effects in bone of cPTH and iPTH treatment remain enigmatic. cPTH (but not iPTH) stimulates T cell production of the osteoclastogenic cytokine TNF¿ through direct continuous PTH signaling in T cells. By contrast, T cells respond to iPTH (but not cPTH) by producing the osteogenic Wnt ligand Wnt10b. We thus hypothesize that the differential effects of cPTH and iPTH are explained by the capacity of continuous and intermittent PTH signaling in T cells to induce TNF and Wnt10b production respectively. Another effect of PTH is to downregulate the production of sclerostin a factor that decreases Wnt signaling in bone cells. Consequently, In Specific Aim 1 we will generate T cells with constitutively active PPR signaling, investigate the effects in bone of continuous PPR signaling in T cells, and determine whether PPR signaling in T cells alters the bone response to cPTH and iPTH through TNF. In Specific Aim 2 we will investigate the effects in bone of overexpression of Wnt10b in T cells, and determine whether T cell produced Wnt10b alters the bone response to cPTH and iPTH. This will be achieved by investigating whether overexpression of Wnt10b in T cells a) causes bone gain in untreated mice, and b) converts the response to cPTH from catabolic to anabolic. In addition we will c) quantify the fraction of the anabolic effect iPTH which is blocked by the overexpression of Wnt10b. This will allow us to determine the contribution of Wnt10b dependent and independent mechanisms to the anabolic activity of iPTH. In Specific Aim 3 we will determine the contribution of T cell produced Wnt10b to the sclerostin-independent bone anabolic effects of iPTH. This will be achieved by treating WT and T cell deficient mice with sclerostin antibody alone, or in combination with iPTH. In addition we will evaluate the effects of iPTH in T cell deficient SOST null and SOST transgenic mice. Lack of information about the mechanism of action of PTH in bone is a critical barrier to progress in the field of bone biology. Our proposal has the potential to decrease this barrier. If the aims of the projects are achieved scientific knowledge about the mechanism of action of PTH will be increased. Novel information about the role of T cells in the mechanism of action of PTH will provide a tangible example of the relevance of the cross-talk between lymphocytes and bone cells.

描述（由申请人提供）：持续的甲状旁腺激素（cPTH）治疗会导致骨质流失，而间歇的甲状旁腺激素（iPTH）治疗会增加骨量，但cPTH和iPTH治疗对骨骼的不同影响的原因仍然是谜。cPTH（而非iPTH）通过T细胞中直接连续的PTH信号传导刺激T细胞产生破骨细胞因子TNF -。相比之下，T细胞通过产生成骨Wnt配体Wnt10b来响应iPTH（而不是cPTH）。因此，我们假设cPTH和iPTH的不同作用可以通过T细胞中连续和间歇PTH信号分别诱导TNF和Wnt10b产生的能力来解释。甲状旁腺激素的另一个作用是下调硬化蛋白的产生，这是一种减少骨细胞中Wnt信号的因子。因此，在Specific Aim 1中，我们将生成具有组成性活性PPR信号传导的T细胞，研究T细胞中连续PPR信号传导对骨的影响，并确定T细胞中的PPR信号传导是否通过TNF改变骨对cPTH和iPTH的反应。在Specific Aim 2中，我们将研究T细胞中Wnt10b过表达对骨的影响，并确定T细胞产生的Wnt10b是否会改变骨对cPTH和iPTH的反应。这将通过研究T细胞中Wnt10b的过表达是否a)导致未治疗小鼠的骨骼增加，以及b)将对cPTH的反应从分解代谢转化为合成代谢来实现。此外，我们将c)量化被Wnt10b过表达阻断的iPTH合成代谢效应的比例。这将使我们能够确定Wnt10b依赖和独立机制对iPTH合成代谢活性的贡献。在特异性目标3中，我们将确定T细胞产生的Wnt10b对iPTH不依赖于硬化蛋白的骨合成代谢作用的贡献。这将通过单独使用硬化蛋白抗体或与iPTH联合治疗WT和T细胞缺陷小鼠来实现。此外，我们将评估iPTH在T细胞缺陷SOST缺失和SOST转基因小鼠中的作用。对甲状旁腺激素在骨中的作用机制缺乏了解是影响骨生物学研究进展的一个重要障碍。我们的提议有潜力