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，并且经常与椎间盘（IVD）的退化性变化有关。除了年龄的危险因素外，IVD或相邻终结物的机械负荷和遗传倾向损伤还可以启动退化过程。到目前为止，关于补体系统可能参与IVD变性，知之甚少。唯一针对该主题的研究报告了末端补体复合物（TCC，C5B-9）在正常IVD中的沉积。补体系统的激活是由各种触发器启动的，其中一些（免疫复合物，特定的基质成分/片段，晶体沉积，组织蛋白酶D）与椎间盘变性有关。我们可以证实TCC在人类退化的IVD中的沉积，尤其是在核核的细胞簇中。因此，该项目的核心假设是，补体系统，尤其是TCC在IVD降级的发展和/或进展中起着相关作用。通过使用临床组织样品，先前在体外建立和C6缺陷的兔模型，该模型无法构成TCC中心问题1）TCC是否在盘式变性中起着核心作用，2）哪些机制在IVD和3）中导致TCC生物学后的TCC-Formation in IVD-Cells in IVD-Cells in IVD-Cells in IVD-Cells在IVD中导致哪些机制进行补体激活。在一种翻译方法中，将确定IVD组织中的补体成分，激活产物和调节剂，并与不同的临床情况相关。如果IVD细胞中补体成分或调节剂的表达受到退化盘中存在的促炎环境的影响，则可以阐明。用于TCC形成的基于IVD细胞的ELISA将用于研究致病因素对TCC激活的贡献。此外，IVD细胞中TCC形成引起的分子过程以及药理学抑制TCC形成的治疗作用将在体外表征。 C6缺陷兔代表了一个独特的模型，用于测试TCC形成和创伤引起的IVD降级的因果关系。这将通过一项包括IVD - 功能和终板钻孔的动物研究来实现，以相同的遗传背景的C6充足和缺乏的兔子进行钻探。总体而言，该项目的结果将使对IVD脱生的发病机理有更好的了解，并可能定义新的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