Role of the terminal complement complex in intervertebral disc degeneration

末端补体复合物在椎间盘退变中的作用

• 批准号: 374974913
• 负责人: Professor Dr. Rolf Erwin Brenner
• 金额: --
• 依托单位: Institut für Unfallchirurgische Forschung und Biomechanik
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/374974913?language=en
• 关键词: Role; terminal; complement; complex; intervertebral

Chronic low back pain is one of the most common human health problems and frequently associated with degenerative changes of the intervertebral disc (IVD). Besides the risk factors age, mechanical loading and genetic predisposition injuries of the IVD or adjacent endplates can initiate the degenerative process. So far, little is known about a possible involvement of the complement system in IVD degeneration. The only study addressing this topic reported a deposition of the terminal complement complex (TCC, C5b-9) in degenerated but not in normal IVDs. Activation of the complement system is initiated by various triggers, several of which (immune complexes, specific matrix components/fragments, crystal depositions, cathepsin D) are known to be associated with disc degeneration. We could confirm the deposition of TCC in human degenerated IVDs especially in cell clusters of the nucleus pulposus. Thus, the central hypothesis of the project, that the complement system, especially the TCC, plays a relevant role in the development and/or progression of IVD-degeneration is well founded. By the use of clinical tissue samples, previously established in vitro-assays and a C6-deficient rabbit model which cannot form the TCC the central questions 1) whether the TCC plays a central role in disc degeneration, 2) which mechanisms lead to complement activation in the IVD and 3) which cell-biologic consequences are induced by TCC-formation in IVD-cells shall be addressed. In a translational approach, the presence of complement components, activation products and regulators in IVD tissue will be determined and correlated to different clinical situations. It will be clarified if the expression of complement components or regulators in IVD-cells is influenced by a pro-inflammatory milieu present in degenerated discs. An IVD-cell-based ELISA for TCC-formation will be used to study the contribution of pathogenic factors to the activation of TCC. Furthermore, the molecular processes induced by TCC-formation in IVD-cells as well as therapeutic effects of pharmacological inhibition of TCC-formation will be characterized in vitro. The C6-deficient rabbit represents a unique model to test for a causal relationship of TCC-formation and trauma-induced IVD-degeneration. This will be achieved by an animal study comprising IVD-puncture and endplate drilling in C6-sufficient and -deficient rabbits of identical genetic background. Overall, the results of the project will lead to a better understanding of the pathogenesis of IVD-degeneration and might define the molecular basis for new therapeutic strategies.

慢性腰痛是最常见的人类健康问题之一，通常与椎间盘（IVD）退行性变化相关。除了年龄的危险因素外，IVD 或邻近终板的机械负荷和遗传易感性损伤也可能引发退行性过程。迄今为止，人们对补体系统可能参与 IVD 变性知之甚少。解决该主题的唯一研究报告了末端补体复合物（TCC，C5b-9）在退化中沉积，但在正常 IVD 中没有沉积。补体系统的激活由各种触发因素启动，其中一些触发因素（免疫复合物、特定基质成分/片段、晶体沉积、组织蛋白酶 D）已知与椎间盘退变有关。我们可以证实TCC在人类退化IVD中的沉积，尤其是在髓核细胞簇中的沉积。因此，该项目的中心假设，即补体系统，特别是 TCC，在 IVD 变性的发生和/或进展中发挥相关作用，是有充分根据的。通过使用临床组织样本、先前建立的体外测定和不能形成 TCC 的 C6 缺陷兔模型，中心问题 1) TCC 是否在椎间盘退变中发挥核心作用，2) 哪些机制导致 IVD 中的补体激活，3) IVD 细胞中 TCC 形成诱导哪些细胞生物学后果。在转化方法中，将确定 IVD 组织中补体成分、激活产物和调节剂的存在，并将其与不同的临床情况相关联。将会澄清 IVD 细胞中补体成分或调节因子的表达是否受到退变椎间盘中存在的促炎环境的影响。基于 IVD 细胞的 TCC 形成 ELISA 将用于研究致病因素对 TCC 激活的贡献。此外，IVD细胞中TCC形成诱导的分子过程以及TCC形成的药理抑制的治疗效果将在体外进行表征。 C6 缺陷兔代表了一种独特的模型，用于测试 TCC 形成与创伤引起的 IVD 变性之间的因果关系。这将通过一项动物研究来实现，该研究包括对具有相同遗传背景的 C6 充足和缺乏的兔子进行 IVD 穿刺和终板钻孔。总体而言，该项目的结果将有助于更好地了解 IVD 变性的发病机制，并可能确定新治疗策略的分子基础。

项目成果

EUROSPINE 2019: Oral Presentations

EUROSPINE 2019：口头报告

• DOI: 10.1007/s00586-019-06101-2
• 发表时间: 2019
• 期刊: European Spine Journal
• 影响因子: 2.8
• 作者: Teixeira GQ;Yong Z;Goncalves RM;Kuhn A;Nerlich A;Barth T;Mauer UM;Ignatius A;Brenner R;Neidlinger-Wilke C
• 通讯作者: Neidlinger-Wilke C

Mesenchymal stem cell secretome decreases the inflammatory response in annulus fibrosus organ cultures.

• DOI: 10.22203/ecm.v042a01
• 发表时间: 2021-07
• 期刊: European cells & materials
• 影响因子: 3.1
• 作者: C. Neidlinger-Wilke;A. Ekkerlein;R. Gonçalves;J. Ferreira;A. Ignatius;H. Wilke;G. Teixeira

EUROSPINE Meeting 2020: Abstracts Virtual Annual Meeting, 6–9 October

EUROSPINE 会议 2020：摘要虚拟年会，10 月 6 日至 9 日

• DOI: 10.1007/s00586-020-06683-2
• 发表时间: 2020
• 期刊: European Spine Journal
• 影响因子: 2.8
• 作者: Teixeira GQ;Yong Z;Kuhn A;Mauer UM;Ignatius A;Brenner R;Neidlinger-Wilke C
• 通讯作者: Neidlinger-Wilke C

Terminal complement complex formation is associated with intervertebral disc degeneration

末端补体复合物的形成与椎间盘退变有关

• DOI: 10.1007/s00586-020-06592-4
• 发表时间: 2021
• 期刊: European Spine Journal
• 影响因子: 2.8
• 作者: Teixeira GQ;Yong Z;Goncalves RM;Kuhn A;Riegger-J;Brisby H;Henriksson HB;Barth T;Mauer UM;Ignatius A;Brenner R;Neidlinger-Wilke C
• 通讯作者: Neidlinger-Wilke C