Bone Formation and the Immuno-Skeletal Interface

骨形成和免疫骨骼界面

基本信息

批准号：
10045551
负责人：
Mervyn Neale Weitzmann
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10045551
关键词：
Age Aging Anabolic Agents Anabolism Animal Model Anti-Inflammatory Agents Antibodies Antigen-Presenting Cells Antigens Bass Biological Assay Bone Density Bone Regeneration Bone Resorption Bone remodeling CD28 gene CD8-Positive T-Lymphocytes CD8B1 gene CREB1 gene CRISPR/Cas technology CTLA4-Ig Cells Clinical Clonal Expansion Collagen Arthritis Cyclic AMP Cyclic AMP Response Element Cyclic AMP-Dependent Protein Kinases Development Disease Dose Dual-Energy X-Ray Absorptiometry Economic Burden Elderly Elements Enzyme-Linked Immunosorbent Assay Event FDA approved FOXP3 gene Female Flow Cytometry Forteo Fracture Future Gap Junctions General Population Generations Goals Health Expenditures Healthcare Systems Hip Fractures Human Hysteria IL2RA gene Immune Immune system Immunophenotyping Immunosuppressive Agents In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Injections Integrated Health Care Systems Knock-out Knockout Mice Lead Leadership Ligands Luciferases Mediating Mediator of activation protein Medical Medical Care Costs Metabolic Methods Molecular Analysis Morbidity - disease rate Mus Mutation Analysis Null Lymphocytes Operative Surgical Procedures Osteoblasts Osteogenesis Osteoporosis Ovalbumin PTH gene Pathway interactions Patients Pentoxifylline Pharmaceutical Preparations Pharmacology Physiological Population Study Prevention Prevention therapy Production Quality of life Rehabilitation therapy Reporter Reporting Reverse Transcriptase Polymerase Chain Reaction Rheumatoid Arthritis Role Rolipram Schedule Signal Transduction Signal Transduction Pathway Skeletal system Skeleton Societies Stains Stimulus Structure Surface T cell anergy T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Transgenic Mice Transplantation Vaccination Validation Veterans Viral Antigens WNT Signaling Pathway WNT10B gene Woman Work Wrestling aged anergy base bisphosphonate bone bone loss bone mass bone turnover compliance behavior cost cytokine disability drug repurposing improved in vivo indexing inflammatory milieu male men microCT mortality mouse model novel older men older women parathyroid hormone (1-34)peer prevent programs promoter prospective reconstitution response side effect skeletal

项目摘要

Osteoporosis is endemic in the US and other Western societies and fractures are a serious medical problem among aging Veterans and their peers in the general population with 1 in 2 females and 1 in 4 males over the age of 50 projected to suffer an osteoporosis related bone fracture in their lifetimes. Fractures lead to huge healthcare expenditures, loss of mobility and significant morbidity. Hip fractures almost always require major surgery and mortality rates are extremely high in aged individuals following surgery, approaching 24% in the general population and reaching as high as 32% in male veterans. Historically, anti-resorptive drugs (such as bisphosphonates) have been the mainstay of anti-osteoporosis therapy/fracture prevention and although these agents stall further bone degeneration and lead to an increase in bone mineral density, they are inefficient at restoring high quality, remodelled bone and many patients treated with these drugs ultimately still go on to sustain a fracture. Compliance in taking anti-resorptive agents is furthermore extremely poor with multiple large population studies conducted in major healthcare systems all reporting abysmal patient compliance with typically 75% of patients discontinuing their anti-resorptive medications within a year of initiation, due to inconvenient administration schedules, side-effects and costs. Recently, rare but potentially serious complications of long term anti-resorptive use have led to hysteria among the public and an unprecedented and alarming retreat from pharmacological fracture prevention therapy is now underway. This has led to a "call for action" by the ASBMR leadership, however clearly, other pharmacological alternatives are now even more urgently needed. In contrast to anti-catabolic agents, drugs based on parathyroid hormone (PTH) such as Teriparatide (PTH (1-34)) and Preotact (PTH (1-84)), are the only FDA approved bone anabolic therapies capable of stimulating bone formation and reversing bone loss, thus reducing the odds of fracture. Although additional bone anabolic drugs are in development, potential side-effects have indefinitely delayed final FDA approval of Amgen’s anti-sclerostin antibody Romosozumab. PTH-based anabolics, like Teriparatide, are thus likely to remain the only available bone anabolic agents for the near future. Teriparatide however, has significant limitations of its own that have constrained its wider application, including inconvenient daily injection and rapidly waning efficacy. During the tenure of this Merit program we made the unexpected discovery that the pharmacological T cell immunosuppressant Abatacept (CTLA4-Ig), used in the therapy of inflammatory diseases, such as rheumatoid arthritis, mediates a bone anabolic signal. When Abatacept renders T cells dormant (anergic), it transforms them into Wnt10b secreting cells. Wnt10b is a ligand for the Wnt-signal transduction pathway, that promotes bone formation by stimulating differentiation and activity of osteoblasts. Teriparatide itself promotes bone formation in part by upregulating Wnt10b in T cells. We hypothesized, and demonstrated, that by priming T cells to undergo anergy, Abatacept is able to amplify the anabolic activity of Teriparatide in mice. As Abatacept alone has more modest bone anabolic activity than Teriparatide alone, our Merit renewal proposes to investigate methods to intensify the bone anabolic activity of Abatacept, Teriparatide and Abatacept and Teriparatide together. In Aim 1 we will investigate whether raising basal T cell activation state can amplify the bone anabolic activities of Abatacept and Teriparatide, alone and in combination, by enhancing the capacity of T cells to secrete enhanced concentrations of Wnt10b in response to these stimuli. In Aim 2 we will examine if Abatacept and/or Teriparatide enhance bone anabolic activity in the context of an inflammatory environment such as rheumatoid arthritis, using the collagen induced arthritis mouse model. Because T cell anergy is dependent on sustained cAMP signalling and the Wnt10b gene promoter is regulated in part through cAMP response elements (CREs), Aim 3 will examine the role of cAMP signalling in T cells and Wnt10b generation by anergic T cells.

骨质疏松症在美国和其他西方社会很流行，骨折是一个严重的医疗问题在老年退伍军人及其同龄人中，四分之一的女性和四分之一的男性 50岁预计一生中会遭受骨质疏松症相关的骨折，骨折会导致巨大的骨折。医疗支出、行动能力丧失和严重的髋部骨折几乎总是需要严重的。老年人的手术和术后死亡率极高，在老年人中接近 24% 一般人群中，男性退伍军人中这一比例高达 32%。双膦酸盐）一直是抗骨质疏松症治疗/骨折预防的支柱，尽管这些药物可以阻止进一步的骨退化并导致骨矿物质密度增加，但它们在以下方面效率低下：恢复高质量、重塑的骨骼，许多接受这些药物治疗的患者最终仍然继续维持此外，由于多发性骨折，服用抗骨吸收药物的依从性极差。在主要医疗保健系统中进行的人口研究均报告患者对通常情况的依从性极差 75% 的患者由于不方便而在开始服用抗骨吸收药物后一年内停止使用给药时间表、副作用和费用最近出现了罕见但可能严重的长期并发症。抗吸收剂的使用导致公众歇斯底里，并导致前所未有的、令人震惊的撤退目前正在进行药物性骨折预防治疗，ASBMR 对此“呼吁采取行动”。但显然，相比之下，现在更迫切需要其他药物替代方案。抗分解代谢药物、基于甲状旁腺激素 (PTH) 的药物，如特立帕肽 (PTH (1-34)) 和 Preotact (PTH (1-84)) 是 FDA 批准的唯一能够刺激骨形成的骨合成代谢疗法并逆转骨质流失，从而降低骨折的几率，尽管正在使用其他骨合成代谢药物。由于潜在的副作用无限期推迟了 FDA 对安进抗硬化素的最终批准因此，基于 PTH 的合成代谢药物（如特立帕肽）可能仍然是唯一可用的。然而，在不久的将来，特立帕肽本身也有很大的局限性。日常注射不方便且疗效迅速减弱等限制了其更广泛的应用。在这个优异计划的任期内，我们意外地发现了药理 T 细胞免疫抑制剂阿巴西普 (CTLA4-Ig)，用于治疗炎症性疾病，例如类风湿病关节炎，介导骨合成代谢信号。当阿巴西普使 T 细胞休眠（无能）时，它会改变它们。进入 Wnt10b 分泌细胞 Wnt10b 是 Wnt 信号转导途径的配体，可促进骨生长。特立帕肽本身通过刺激成骨细胞的分化和活性来促进骨形成。我们通过启动 T 细胞经历并证明了这一点。由于阿巴西普单独使用，阿巴西普能够增强特立帕肽的合成代谢活性。与单独使用特立帕肽相比，骨合成代谢活性适中，我们的优点更新建议是研究方法 In Aim 增强阿巴西普、特立帕肽以及阿巴西普和特立帕肽一起的骨合成代谢活性。 1 我们将研究提高基础T细胞活化状态是否可以增强骨合成代谢活性阿巴西普和特立帕肽单独或联合使用，通过增强 T 细胞分泌增强型在目标 2 中，我们将检查阿巴西普和/或特立帕肽是否对这些刺激作出反应。在类风湿性关节炎等炎症环境中增强骨合成代谢活性，使用因为 T 细胞无反应性依赖于持续的 cAMP 信号传导。 Wnt10b 基因启动子部分通过 cAMP 反应元件 (CRE) 进行调节，目标 3 将检查 cAMP 信号传导在 T 细胞中的作用以及无能 T 细胞产生 Wnt10b。