The role of the intervertebral disc cartilage catabolites in Modic type 1 changes

Modic type 1 changes (MC1) are bone marrow lesions adjacent to intervertebral discs with inflamed and degenerated endplates. Proteomic analysis revealed that MC1 discs contain enriched extracellular matrix (ECM) fragments and an overexpressed protease. In vitro experiments demonstrated this protease's ability to generate these fragments, which activate toll-like receptor 2 (TLR2), acting as damage-associated molecular patterns (DAMPs). Endplate cells, especially in MC1, were identified to express numerous TLRs, with TLR2 being overexpressed. TLR2 activation by ECM-derived DAMPs induced inflammation and catabolism, especially in MC1 endplate cells. Blocking TLR2 prevented this effect. Similarly, stimulating healthy endplate tissue with TLR2 ligands led to inflammation and degeneration, resembling MC1 characteristics. TLR2 inhibitors effectively halted these pathological processes. In summary, MC1 disc degeneration involves overexpressed matrix proteases generating ECM-derived DAMPs, triggering inflammation and degradation in adjacent endplates through TLR2 activation, which can be mitigated with TLR2 inhibitors.

Inflammation of the vertebral endplate and bone marrow are often seen in patients with chronic low back pain on MRI. These changes are called Modic type 1 changes (MC1). They occur adjacent to a degenerated intervertebral disc. In most cases disc degeneration does not cause pain. In contrast, MC1 are in most cases a source of pain. The aim of this study was to identify molecules that are overrepresented in MC1 and cause inflammation, and to find ways how to inhibit this process.

By analysing tissue from patients with MC1, we identified fragments of proteins that are much more abundant in MC1 tissue. We showed that these fragments can cause inflammation and degenerative changes which are typical for MC1. We identified the molecular mechanisms how these protein fragments cause inflammation and showed that blocking these mechanisms prevents inflammation and degenerative changes.

• Mengis, T., Herger, N., Heggli, I., Devan, J., Spirig, J. M., Laux, C. J., Brunner, F., Farshad, M., Distler, O., & Dudli, S. (2023). Bone marrow stromal cells in Modic type 1 changes promote neurite outgrowth. Frontiers in Cell and Developmental Biology, 11. doi.org/10.3389/fcell.2023.1286280
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• Mengis T, Zajac N, Bernhard L, et al. Intervertebral disc microbiome in Modic changes: Lack of result replication underscores the need for a consensus in low-biomass microbiome analysis. JOR Spine. 2024; 7(2):e1330. doi:10.1002/jsp2.1330
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Abstracts

• Mengis T, Heggli I, Herger N, et al. Proceeding of the eCM 2022 conference, Davos, June 15-18. Stromal Cells in Modic Type 1 Change Bone Marrow Promote Neurite Outgrowth.
• Mengis T, Heggli I, Herger N, et al. AB1398 STROMAL CELLS IN MODIC TYPE 1 CHANGE BONE MARROW PROMOTE NEURITE OUTGROWTH. Ann Rheum Dis. 2023;82:1928.
• Mengis T, Heggli I, Herger N, et al. POS0416 DISTINCT DEGENERATION MECHANISMS IN INTERVERTEBRAL DISCS ADJACENT TO MODIC CHANGES. Ann Rheum Dis. 2023;82:463-464.
• Mengis T, Heggli I, Herger N, et al. Proceedings of the Annual Meeting 2023 of ORS, Dallas, February 10-14. Stromal Cells in Modic Type 1 Change Bone Marrow Promote Neurite Outgrowth. Poster No. 1912
• Mengis T, Heggli I, Herger N, et al. Proceedings of the Annual Meeting 2023 of ORS, Dallas, February 10-14. Increased Proteolytic Activity In 'Modic Disc' Yields More Pro-Inflammatory Acting ECM Fragments. Poster No. 1915
• Mengis T, Heggli I, Herger N, et al. Proceedings of Spineweek 2023, Melbourne, May 1-5. Stromal Cells in Modic Type 1 Change Bone Marrow Promote Neurite Outgrowth. Poster No. 12
• Mengis T, Heggli I, Herger N, et al. Proceedings of Spineweek 2023, Melbourne, May 1-5. Distinct proteolytic activity creates a unique ‘Modic disc’ degradome. Poster No. 18