Bone Formation and the Immuno-Skeletal Interface

骨质疏松症在美国和其他西方社会很普遍，骨折是一个严重的医疗问题 在老年退伍军人和他们的同龄人中，1/2的女性和1/4的男性超过 预计50岁的人一生中将遭受骨质疏松相关的骨折。骨折导致巨大 医疗费用、行动不便和严重的发病率。髋部骨折几乎总是需要大量的 老年人的手术和死亡率极高，手术后死亡率接近24%。 在普通人群中，男性退伍军人比例高达32%。从历史上看，抗吸收药物(如 双膦酸盐)一直是抗骨质疏松治疗/骨折预防的中流砥柱，尽管这些 药物会延缓进一步的骨骼退化，并导致骨密度的增加，它们在 恢复高质量的、重塑的骨骼，许多接受这些药物治疗的患者最终仍将继续 骨折。此外，服用抗吸收药物的依从性极差，有多个 在主要医疗保健系统进行的人口研究都报告了患者对典型的 75%的患者在开始服药一年内因不便而停止服用抗吸收药物 给药时间表、副作用和成本。最近，罕见但潜在严重的长期并发症 反再吸收使用在公众中导致了歇斯底里，并史无前例地、令人震惊地从 目前正在进行预防骨折的药物治疗。这导致了ASBMR的“行动呼吁” 领导力，无论多么明显，现在更迫切地需要其他药物替代方案。相比之下， 对于抗分解代谢药物，以甲状旁腺素(PTH)为基础的药物，如Teriparatide(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疗法 并逆转骨质流失，从而降低骨折的几率。尽管有更多的骨合成新药问世 开发，潜在的副作用无限期地推迟了FDA对安进的抗硬化素的最终批准 Romosozumab抗体。因此，以甲状旁腺素为基础的合成代谢药物，如特立帕替德，可能仍然是唯一可用的 骨合成代谢药在不久的将来。然而，teriparatide本身有很大的局限性， 限制了其更广泛的应用，包括日常注射不便和药效迅速减弱。在.期间 在这个功绩计划的任期内，我们有了一个意想不到的发现，即药理T细胞 免疫抑制剂abatacept(CTLA4-Ig)，用于治疗类风湿等炎症性疾病 关节炎，调节骨骼合成代谢的信号。当Abatacept使T细胞休眠(无能)时，它会将它们转化为 进入Wnt10b分泌细胞。Wnt10b是Wnt-信号转导通路的配体，它促进骨骼 通过刺激成骨细胞的分化和活性形成。Teriparatide本身促进大鼠骨形成 部分是通过上调T细胞中Wnt10b的表达。我们假设并证明了，通过启动T细胞来经历 无能，abatacept能够放大Terparatide在小鼠体内的合成代谢活性。因为单是abatacept一项就有更多 适度的骨合成代谢活性比单独使用Terparatide更好，我们的优点更新建议研究方法 联合应用阿巴达塞、特瑞帕特、阿巴特塞特和特瑞帕特，增强骨合成代谢活性。在AIM 1我们将研究提高基础T细胞激活状态是否可以放大骨合成代谢活性。 Abatacept和Terparatide单独或联合应用可增强T细胞的分泌能力 WNT10b的浓度对这些刺激的反应。在目标2中，我们将检查abatacept和/或teriparatide 在炎性环境(如类风湿性关节炎)中增强骨合成代谢活性 胶原性关节炎小鼠模型。因为T细胞无能依赖于持续的cAMP信号 而Wnt10b基因的启动子部分是通过cAMP反应元件(Cres)来调节的，Aim 3将研究 CAMP信号在T细胞和无能T细胞产生WNT10b中的作用

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.