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（由申请人提供）：连续 PTH (cPTH) 治疗会导致骨质流失，而间歇性 PTH (iPTH) 治疗会增加骨量，但 cPTH 和 iPTH 治疗对骨的影响不同的原因仍然是个谜。 cPTH（但不是 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（但不响应 cPTH）。因此，我们假设 cPTH 和 iPTH 的不同作用可以通过 T 细胞中连续和间歇性 PTH 信号传导分别诱导 TNF 和 Wnt10b 产生的能力来解释。 PTH 的另一个作用是下调硬化素的产生，硬化素是减少骨细胞中 Wnt 信号传导的因素。因此，在具体目标 1 中，我们将生成具有持续活跃的 PPR 信号传导的 T 细胞，研究 T 细胞中连续 PPR 信号传导对骨骼的影响，并确定 T 细胞中的 PPR 信号传导是否通过 TNF 改变骨骼对 cPTH 和 iPTH 的反应。在具体目标 2 中，我们将研究 T 细胞中 Wnt10b 过度表达对骨骼的影响，并确定 T 细胞产生的 Wnt10b 是否会改变骨骼对 cPTH 和 iPTH 的反应。这将通过研究 T 细胞中 Wnt10b 的过度表达是否 a) 导致未经治疗的小鼠骨增加，b) 将对 cPTH 的反应从分解代谢转变为合成代谢来实现。此外，我们将 c) 量化被 Wnt10b 过度表达阻断的合成代谢效应 iPTH 的比例。这将使我们能够确定 Wnt10b 依赖性和独立机制对 iPTH 合成代谢活性的贡献。在具体目标 3 中，我们将确定 T 细胞产生的 Wnt10b 对 iPTH 的不依赖于硬化素的骨合成代谢作用的贡献。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，我们将评估 iPTH 对 T 细胞缺陷的 SOST 无效小鼠和 SOST 转基因小鼠的影响。缺乏有关 PTH 在骨中作用机制的信息是骨生物学领域进展的关键障碍。我们的建议有潜力 来减少这个障碍。如果项目的目标得以实现，有关 PTH 作用机制的科学知识将会增加。关于 T 细胞在 PTH 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。 公共健康相关性：PTH 作用机制的新发现与公共健康相关，因为它可能导致骨质疏松症新治疗靶点的确定。我们的研究还可能为增强间歇性 PTH 治疗的合成代谢活性的策略提供见解。其中一种策略可能是增加 T 细胞产生 Wnt 配体。