Bone Formation and the Immuno-Skeletal Interface

骨质疏松症在美国和其他西方社会是一种地方病，骨折是一个严重的医学问题 在老年退伍军人和他们的同龄人在一般人群中，1/2的女性和1/4的男性超过 预计50岁的人在其一生中遭受骨质疏松症相关的骨折。骨折导致巨大的 医疗保健支出，丧失流动性和严重的发病率。髋部骨折几乎总是需要 老年人手术后的手术率和死亡率极高， 在一般人群中，男性退伍军人的比例高达32%。从历史上看，抗吸收药物（如 二膦酸盐）已经成为抗骨质疏松症治疗/骨折预防的支柱， 药物阻止了进一步的骨退化并导致骨矿物质密度的增加，但它们在 恢复高质量，重塑骨和许多患者治疗这些药物最终仍然继续维持 骨折此外，服用抗吸收剂的依从性极差， 在主要的医疗保健系统中进行的人群研究都报告了患者对通常 75%的患者在开始治疗后一年内因不方便而停用抗吸收药物 管理时间表，副作用和成本。最近，罕见但可能严重的长期并发症 抗吸收剂的使用导致了公众的歇斯底里， 目前正在进行药物骨折预防治疗。这导致了ASBMR的“行动呼吁” 然而，显然，现在更迫切需要其他药物替代品。相比之下 抗分解代谢剂，基于甲状旁腺激素（PTH）的药物，如特立帕坦（PTH（1-34））， Preotact（PTH（1-84））是唯一FDA批准的能够刺激骨形成的骨合成代谢疗法 逆转骨质流失从而降低骨折几率虽然额外的骨合成代谢药物是在 潜在的副作用无限期地推迟了FDA对安进抗硬化素的最终批准 抗体Romosozumab。基于PTH的合成代谢药物，如Teriparbal，因此可能仍然是唯一可用的 骨合成代谢剂。然而，Teriparavirus具有其自身的重大局限性， 限制了其更广泛的应用，包括不方便的日常注射和迅速减弱的功效。期间 在这个Merit项目的任期内，我们意外地发现， 免疫抑制剂阿巴西普（CTLA 4-IG），用于治疗炎性疾病，如类风湿性关节炎 关节炎，介导骨合成代谢信号。当阿巴西普使T细胞处于休眠状态（无反应性）时， Wnt 10 b分泌细胞Wnt 10 b是Wnt信号转导途径的配体，其促进骨形成 通过刺激成骨细胞的分化和活性形成。Teriparbital本身促进骨形成， 部分通过上调T细胞中的Wnt 10 b。我们假设，并证明，通过启动T细胞进行 在无反应性的情况下，阿巴西普能够放大特立帕鲁肽在小鼠中的合成代谢活性。由于阿巴西普单独具有更多 适度的骨合成代谢活性，我们的Merit更新建议研究方法， 增强阿巴西普、特立帕鲁和阿巴西普与特立帕鲁一起的骨合成代谢活性。在Aim中 1我们将研究是否提高基础T细胞活化状态可以放大骨合成代谢活动， 阿巴西普和特立帕鲁肽，单独和组合，通过增强T细胞分泌增强的T细胞的能力， Wnt 10 b的浓度响应于这些刺激。在目标2中，我们将检查阿巴西普和/或特立帕鲁肽是否 在炎性环境如类风湿性关节炎的情况下增强骨合成代谢活性， 胶原诱导的关节炎小鼠模型。因为T细胞无反应性依赖于持续的cAMP信号传导 Wnt 10 b基因启动子部分通过cAMP反应元件（克雷斯）调节，Aim 3将检测 cAMP信号传导在T细胞中的作用和无反应性T细胞产生Wnt 10 b。

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.