Project Details
Projekt
Role of the terminal complement complex in intervertebral disc degeneration
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
from 2017 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 374974913
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.
DFG Programme
Research Grants
