Bone Formation and the Immuno-Skeletal Interface

骨形成和免疫骨骼界面

• 批准号: 10296650
• 负责人: Mervyn Neale Weitzmann
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 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/10296650
• 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; 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

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和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，有1分之一的女性和1分之一的男性中有1名 50岁的预计将在其一生中患有骨质疏松症相关的骨折。骨折导致巨大 医疗保健支出，流动性丧失和大量发病率。髋部骨折几乎总是需要专业 手术后，年龄个体的手术和死亡率极高，接近24％ 一般人口，男性退伍军人高达32％。从历史上看，抗抑郁药（例如 双膦酸盐）一直是抗骨质疏松疗法/骨折预防的中流 代理商停滞了进一步的骨变性并导致骨矿物质密度的增加，它们在 恢复高质量，改建的骨骼，许多接受这些药物治疗的患者最终仍继续维持 断裂。此外，服用抗敏化剂的依从性非常贫穷，多个大 在主要医疗系统中进行的人口研究，所有报告都报告糟糕的患者符合依从性 由于不便 管理时间表，副作用和成本。最近，长期罕见但潜在的严重并发症 反应使用的使用导致公众中的歇斯底里症，并从未有过前所未有的令人震惊的撤退 药理预防疗法现在正在进行中。这导致了ASBMR的“行动呼吁” 无论如何，领导力现在更加迫切需要其他药物替代方案。相比之下 对于抗代谢剂，基于甲状旁腺马的药物（PTH），例如Teriparatide（PTH（1-34））和 前动物（PTH（1-84））是唯一能够刺激骨形成的FDA批准的骨合成代谢疗法 逆转骨质流失，从而减少了断裂的几率。尽管其他骨合成代谢药物仍在 开发，潜在的副作用无限期地延迟了Amgen抗骨杆菌素的最终FDA批准 抗体romosozumab。因此，基于PTH的合成代谢，例如Teriparatide，可能仍然是唯一可用的 不久的将来的骨合代代理。然而，teriparatide具有重大局限性 限制了其更广泛的应用，包括每日不方便和迅速减弱的效率。在 这个优点计划的任期，我​​们意外发现的是药物T细胞 免疫抑制剂abatacept（CTLA4-IG）用于炎症性疾病的治疗，例如类风湿病 关节炎，介导骨合成代谢信号。当Abatacept呈现T细胞休眠（厌食）时，它会改变它们 进入Wnt10b分泌细胞。 Wnt10b是Wnt信号转移途径的配体，可促进骨骼 通过刺激成骨细胞的分化和活性来形成。 Teriparatide本身促进了骨形成 部分通过上调T细胞中的Wnt10b。我们假设并证明了通过启动T细胞进行的 Anergy，Abatacept能够扩增小鼠Teriparatide的合成代谢活性。因为仅abatacept就有更多 比单独的teriparatide相比，适度的骨合代活性是我们的优点续签建议，以研究方法 加强Abatacept，Teriparatide和Abatacept和Teriparatide的骨合成代谢活性。目标 1我们将研究提高基本T细胞激活状态是否可以扩增 通过增强T细胞增强的T细胞的能力，单独和组合abatacept和Teriparatide Wnt10b响应这些刺激的浓度。在AIM 2中，我们将检查Abatacept和/或Terriparatide是否 在炎症环境（例如类风湿关节炎）的背景下，增强骨合成代谢活性，使用 胶原蛋白诱导的关节炎小鼠模型。因为T细胞消极取决于持续的cAMP信号传导 WNT10B基因启动子部分通过cAMP响应元素（CRES）进行调节，AIM 3将检查 cAMP信号传导在T细胞和Wnt10b通过厌食T细胞产生的作用。

项目成果

B Cell Production of Both OPG and RANKL is Significantly Increased in Aged Mice.

• DOI: 10.2174/1876525401406010008
• 发表时间: 2014
• 期刊: The Open bone journal
• 作者: Li Y;Terauchi M;Vikulina T;Roser-Page S;Weitzmann MN
• 通讯作者: Weitzmann MN

Immune activation mediated change in alpha-1-acid glycoprotein: impact on total and free lopinavir plasma exposure.

• DOI: 10.1177/0091270010385118
• 发表时间: 2011-11
• 期刊: Journal of clinical pharmacology
• 影响因子: 2.9
• 作者: Ofotokun I;Lennox JL;Eaton ME;Ritchie JC;Easley KA;Masalovich SE;Long MC;Acosta EP
• 通讯作者: Acosta EP

New method to prepare very stable and biocompatible fluorescent silica nanoparticles.

• DOI: 10.1039/b902195g
• 发表时间: 2009-05-28
• 期刊: Chemical communications (Cambridge, England)
• 作者: Ha SW;Camalier CE;Beck GR Jr;Lee JK
• 通讯作者: Lee JK

CTLA-4Ig-induced T cell anergy promotes Wnt-10b production and bone formation in a mouse model.

• DOI: 10.1002/art.38319
• 发表时间: 2014-04
• 期刊: ARTHRITIS & RHEUMATOLOGY
• 影响因子: 13.3
• 作者: Roser-Page, Susanne;Vikulina, Tatyana;Zayzafoon, Majd;Weitzmann, M. Neale
• 通讯作者: Weitzmann, M. Neale

T cell-expressed CD40L potentiates the bone anabolic activity of intermittent PTH treatment.

• DOI: 10.1002/jbmr.2394
• 发表时间: 2015-04
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Robinson, Jerid W.;Li, Jau-Yi;Walker, Lindsey D.;Tyagi, Abdul Malik;Reott, Michael A.;Yu, Mingcan;Adams, Jonathan;Weitzmann, M. Neale;Pacifici, Roberto
• 通讯作者: Pacifici, Roberto