Terminal Complement Activation Is Induced by Factors Released from Endplate Tissue of Disc Degeneration Patients and Stimulates Expression of Catabolic Enzymes in Annulus Fibrosus Cells

Cells. 2023 Mar 13;12(6):887. doi: 10.3390/cells12060887.


Terminal complement complex (TCC) deposition was identified in human degenerated discs. To clarify the role of terminal complement activation in disc degeneration (DD), we investigated respective activating mechanisms and cellular effects in annulus fibrosus (AF) cells. Isolated cells from human AF, nucleus pulposus (NP), and endplate (EP) were stimulated with human serum alone or with zymosan and treated with either the C3 inhibitor Cp40 or the C5 antibody eculizumab. Complement activation was determined via anaphylatoxin generation and TCC deposition detection. Thereby, induced catabolic effects were evaluated in cultured AF cells. Moreover, C5 cleavage under degenerative conditions in the presence of AF cells was assessed. Zymosan-induced anaphylatoxin generation and TCC deposition was significantly suppressed by both complement inhibitors. Zymosan induced gene expression of ADAMTS4, MMP1, and COX2. Whereas the C3 blockade attenuated the expression of ADAMTS4, the C5 blockade reduced the expression of ADAMTS4, MMP1, and COX2. Direct C5 cleavage was significantly enhanced by EP conditioned medium from DD patients and CTSD. These results indicate that terminal complement activation might be functionally involved in the progression of DD. Moreover, we found evidence that soluble factors secreted by degenerated EP tissue can mediate direct C5 cleavage, thereby contributing to complement activation in degenerated discs.

Keywords: complement inhibition; complement system activation; disc degeneration; inflammation; innate immunity; terminal complement complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annulus Fibrosus*
  • Complement Activation
  • Cyclooxygenase 2 / metabolism
  • Humans
  • Intervertebral Disc Degeneration* / metabolism
  • Intervertebral Disc* / metabolism
  • Matrix Metalloproteinase 1 / metabolism
  • Zymosan / metabolism


  • Matrix Metalloproteinase 1
  • Cyclooxygenase 2
  • Zymosan

Grants and funding

This research was funded by the German Research Foundation, grant number BR 919/12-1, NE 549/6-1. Moreover, this research study was supported by the European Social Fund and by the Ministry of Science, Research and Arts Baden-Württemberg.