T Cells and PTH Induced Bone Loss

T 细胞和 PTH 诱导的骨丢失

• 批准号: 8373360
• 负责人: ROBERTO PACIFICI
• 金额: $ 36.25万
• 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/8373360
• 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; 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. PUBLIC HEALTH RELEVANCE: New discoveries about the mechanism of action of PTH are relevant to public health as it may lead to the identification of novel therapeutic targets for osteoporosis. Our studies may also provide insights on strategies for augmenting the anabolic activity of intermittent PTH treatment. One such strategy could be that of augmenting T cell production of Wnt ligands.

描述(申请人提供)：持续甲状旁腺素(CPTH)治疗导致骨丢失，而间歇甲状旁腺素(IPTH)治疗增加骨量，但cPTH和iPTH治疗在骨中的不同作用的原因仍然是个谜。CPTH(但不是iPTH)通过在T细胞中直接持续的PTH信号刺激T细胞产生破骨细胞因子TNF。相比之下，T细胞对iPTH(但不是cPTH)的反应是通过产生成骨的Wnt配体Wnt10b来实现的。因此，我们假设cPTH和iPTH的不同作用是通过T细胞中持续的和间歇性的PTH信号分别诱导肿瘤坏死因子和WNT10b产生的能力来解释的。甲状旁腺激素的另一个作用是下调硬化素的产生，这是一种减少骨细胞中Wnt信号的因素。因此，在特定的目标1中，我们将产生具有结构性活性的PPR信号的T细胞，研究T细胞中持续的PPR信号在骨中的作用，并确定T细胞中的PPR信号是否通过肿瘤坏死因子改变骨对cPTH和iPTH的反应。在特定的目的2中，我们将研究Wnt10b在T细胞中过表达对骨骼的影响，并确定T细胞产生的Wnt10b是否改变了骨对cPTH和iPTH的反应。这将通过研究Wnt10b在T细胞中的过度表达是否a)导致未经治疗的小鼠的骨骼增加，以及b)将对cPTH的反应从分解代谢转换为合成代谢来实现。此外，我们还将c)量化被Wnt10b过表达所阻断的合成代谢效应iPTH的比例。这将使我们能够确定WNT10b依赖和独立的机制对iPTH合成代谢活性的贡献。在特定的目标3中，我们将确定产生的T细胞WNT10b在iPTH的硬化素非依赖性骨合成代谢效应中的作用。这将通过单独使用硬化素抗体或与iPTH联合治疗WT和T细胞缺陷小鼠来实现。此外，我们还将评估iPTH在T细胞缺陷的SOST缺失和SOST转基因小鼠中的作用。甲状旁腺激素在骨中的作用机制缺乏信息是骨生物学领域取得进展的关键障碍。我们的建议有可能 来降低这一障碍。如果这些项目的目标得以实现，将增加对甲状旁腺素作用机制的科学认识。关于T细胞在甲状旁腺激素作用机制中的作用的新信息将为淋巴细胞和骨细胞之间的相互作用提供一个具体的例子。 公共卫生相关性：关于甲状旁腺素作用机制的新发现与公共健康相关，因为它可能导致确定治疗骨质疏松症的新靶点。我们的研究也可能为提高间歇性甲状旁腺激素治疗的合成代谢活性的策略提供见解。一种这样的策略可能是增加Wnt配体的T细胞产量。