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 · 7 authors, 4 centres

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TL;DR

This preclinical in vitro study used human disc cells to show that factors from degenerated endplate tissue can directly activate the terminal complement system, which in turn stimulates the expression of enzymes involved in disc degeneration.

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This preclinical study investigated the role of terminal complement activation in intervertebral disc degeneration (DD) using an in vitro model with isolated human annulus fibrosus (AF), nucleus pulposus, and endplate (EP) cells. Cells were stimulated with zymosan and human serum to induce complement activation, which was measured via anaphylatoxin generation and terminal complement complex (TCC) deposition. The study found that zymosan stimulation significantly induced gene expression of ADAMTS4, MMP1, and COX2 in AF cells. Inhibition at the C5 level with eculizumab significantly reduced the expression of all three factors, while C3 inhibition with Cp40 only reduced ADAMTS4 expression. Furthermore, EP conditioned medium from DD patients and cathepsin D (CTSD) were shown to directly cleave C5 in AF cell cultures, providing a mechanism for complement activation independent of classical pathways. The findings suggest that terminal complement activation, potentially initiated by factors like CTSD from degenerated tissue, may contribute to the catabolic processes in disc degeneration.

STUDY TYPE

other

SPECIALTY

rheumatology

SUMMARISED BY

AI pipeline

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100% · A

ORIGINAL PAPER

PMC10047197

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

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ABSTRACT

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.

CITATION EXPORT

Amelie Kuhn, Jana Riegger, Graciosa Q. Teixeira et al.. 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). https://doi.org/10.3390/cells12060887

AUTHORS

7 · 4 CENTRES

Amelie Kuhn, Jana Riegger, Graciosa Q. Teixeira, Markus Huber-Lang, John D. Lambris, Cornelia Neidlinger-Wilke, Rolf E. Brenner

1Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, Ulm University, 89081 Ulm, Germany
2Institute of Orthopedic Research and Biomechanics, Trauma Research Centre, Ulm University, 89081 Ulm, Germany
3Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, 89081 Ulm, Germany
4Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

EDITOR / REVIEWER

Maciej Lech, Stefanie Steiger