Variations in fracture healing due to age-dependent changes in the adaptation of immune cells towards the hypoxic environment of the fracture gap

由于免疫细胞对骨折间隙缺氧环境的适应随年龄变化而发生的骨折愈合变化

• 批准号: 353142848
• 负责人: Dr. Timo Gaber
• 金额: --
• 依托单位: Deutsches Rheuma-Forschungszentrum Berlin (DRFZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/353142848?language=en
• 关键词: Variations; fracture; healing; due; age

Today about 20% of the people in Germany are of age 65 or higher with a tendency towards an increasing frequency for the next decades. In 2060 every third will be aged 65 or older. This demographic development will lead to a higher incidence of surgical interventions (such as fracture treatment and arthroplasty) as a result of an impaired or delayed bone healing, a degenerative joint disease, osteoarthrosis or osteoporosis. Therefore, we have an unconditional need to better recognize and understand the cause of an impaired or delayed bone healing in order to develop early diagnosis and an efficient therapy. The initial inflammatory phase of fracture healing is of great importance for clinical outcome while setting the course for the follow-up phases the initial phase is inducing angiogenesis and osteogenesis. Compromising the initial inflammatory phase due to immunosuppression or due to aging-dependent immune senescence results in an impaired or delayed bone healing. Our data and studies from other research groups support the hypothesis that efficacy and quality of fracture healing strongly depends on the bioenergetic adaptation of participating immune cells to the pathophysiological hypoxic environment (<2%O2) in the fracture gap. To address this hypothesis, we will examine cellular and humoral composition of the early fracture hematoma (6h-72h) and its impact on the functionality on immune cells with regard to the age of the patients. Moreover, we will analyze and quantify the age-dependent changes of monocytes and T cells in cellular bioenergetic adaptation towards a hypoxic microenvironment focusing on hypoxia-mediated hypoxia-inducible factor (HIF) pathways. We hypothesize that an increase of age leads to a decrease of cellular adaptation towards hypoxia which results in (i) an augmented innate and/or adaptive effector immune response (in eg. monocytes, neutrophils and CTL, Th17, Th1, respectively) while (ii) control of effector response by regulatory immune cells (eg. Treg) is compromised. Therefore, we further assume that promotion of cellular adaptation towards pathophysiological hypoxia could normalize an aging-dependent excessive and/or deregulated immune response. In a proof-of-principle approach, we aim to force the cellular adaptation towards hypoxia in immune cells of aged donors by using chemical stabilization of HIFs.

今天，德国约有20%的人年龄在65岁或以上，在未来几十年内，这一比例有增加的趋势。到2060年，三分之一的人将年龄在65岁或以上。由于骨愈合受损或延迟、退行性关节病、骨关节病或骨质疏松症，这种人口统计学发展将导致手术干预（如骨折治疗和关节成形术）的发生率更高。因此，我们无条件地需要更好地认识和理解骨愈合受损或延迟的原因，以便开发早期诊断和有效治疗。骨折愈合的初始炎症阶段对临床结果非常重要，同时为后续阶段设定过程，初始阶段是诱导血管生成和骨生成。由于免疫抑制或由于衰老依赖性免疫衰老而损害初始炎症阶段导致骨愈合受损或延迟。我们的数据和其他研究小组的研究支持这一假设，即骨折愈合的疗效和质量在很大程度上取决于参与免疫细胞对骨折间隙中病理生理缺氧环境（<2%O2）的生物能量适应。为了解决这一假设，我们将检查早期骨折血肿（6小时-72小时）的细胞和体液成分及其对免疫细胞功能的影响，与患者的年龄有关。此外，我们将分析和量化单核细胞和T细胞在细胞生物能适应缺氧微环境中的年龄依赖性变化，重点是缺氧介导的缺氧诱导因子（HIF）途径。我们假设年龄的增加导致细胞对缺氧的适应性降低，这导致（i）先天性和/或适应性效应免疫应答增强（例如，单核细胞、嗜中性粒细胞和CTL，分别为Th 17、Th 1），而（ii）通过调节性免疫细胞（例如，Treg）受到损害。因此，我们进一步假设，促进细胞适应病理生理缺氧可以正常化的老化依赖性过度和/或失调的免疫反应。在原理验证方法中，我们的目标是通过使用HIF的化学稳定化来迫使老年供体的免疫细胞中的细胞适应缺氧。