Header

UZH-Logo

Maintenance Infos

The Role of Intervertebral Disc Cartilage Catabolites in Modic Type 1 Changes


Mengis, Tamara. The Role of Intervertebral Disc Cartilage Catabolites in Modic Type 1 Changes. 2024, University of Zurich, Faculty of Science.

Abstract

The thesis investigates the pathobiology of Modic changes (MCs), specifically focusing on Modic type 1 changes (MC1), emphasizing the complexity of the disease. Although MCs manifest as vertebral bone marrow lesions, the inflammation and degeneration observed in the neighboring intervertebral disc and cartilage endplate (CEP) are also closely linked to MCs. However, the underlying mechanisms and how the tissues crosstalk to induce MC development are unclear to this point. Yet, comprehending these pathobiological mechanisms is crucial for the development of targeted therapies, which are currently nonexistent. The thesis explores various aspects of MC1 addressing pathologic processes seen within the MC1 bone marrow, the CEP and the disc. Finally, the project's findings suggest a new disease mechanism for MC1 development initiated through MC1 specific disc degeneration.

Chapter three investigated the impact of bone marrow stromal cells (BMSC) from MC1 on neurite outgrowth, using an in-vitro co-culture system. Multiple studies have reported an elevated presence of nerve fibers in the MC1 bone marrow and endplate, a definitive connection to the underlying cause has not been established. For the first time, the dysregulated MC1 BMSCs were directly linked to increased neurite outgrowth. With this knowledge, an important treatment target has been identified, paving the way for further studies to explore how to mitigate this effect.

The fourth chapter explores the concept of a disc microbiome, particularly focusing on the MC1 and MC2 microbiomes, using metagenomic analysis. The disc microbiome challenges the conventional notion of disc sterility, necessitating clear methodological definitions for further investigation. Although our analysis confirmed the presence of a disc microbiome, the findings deviated from those of previous studies on degenerated MC discs, even after aligning the parameters of bioinformatic analysis to the previous studies. This study underscores the importance of not only standardizing bioinformatic analysis approaches but also further investigating factors that influence the bacterial composition of the disc microbiome. Differences could stem from sample preparation techniques or variations in the geographical and ethnic backgrounds of patients. Once clarified, the exploration of the disc microbiome will unlock numerous opportunities for diagnostic and treatment applications.

The fifth chapter of the thesis highlights the to this point overlooked biological role of CEP cells. The experiments were able to confirm the presence of Toll-like receptors (TLRs) on CEP cells and particularly emphasized the presence of TLR2 as it was the only TLR that was upregulated through direct stimulation. The discovery of TLRs on CEP cells is noteworthy due to their high density compared to the cells in the adjacent disc and their ability to induce inflammation and promote the production of catabolic enzymes, potentially leading to endplate degeneration. This not only enhances our understanding of CEP cells but also reveals novel treatment targets.

The sixth chapter presents the main project of the thesis, which focuses on understanding MC1 pathobiology and proposes a new mechanism for MC1 development beginning with MC1-specific disc degeneration. It is grounded in the fact that although disc degeneration is often observed in the disc adjacent to MC1, not all degenerated discs progress to MC1. The proposed MC1-specific disc degeneration is hypothesized to generate more fragments, triggering inflammation in the adjacent endplate, causing endplate destruction. This ultimately breaches the CEP barrier between the disc and bone marrow, allowing pro-inflammatory fragments (damage associated molecular patterns (DAMPs)) and inflammatory cytokines to spill over into the bone marrow, inducing MC1. Although the study is ongoing, significant discoveries have been made. MC1 discs were found to have a higher abundance of extracellular matrix derived fragments as well a greater abundance of the protease high temperature requirement serine protease 1 (HTRA1) than degenerated nonMC discs. In a subsequent phase, the abundant cartilage intermediate layer protein 1 (CILP1) fragments were successfully replicated by exposure to HTRA1 and were demonstrated to possess pro-inflammatory properties via TLR4 signaling activation, thereby classifying them as DAMPs. A CEP explant model was used to show that TLR activation can induce CEP tissue destruction, connecting the DAMP abundance in the disc to CEP damage. However, further experiments are necessary to address the gaps within the proposed mechanism.

MC1 is a pathology associated with distinct inflammatory and pain-related processes, suggesting it could and should be treated specifically. This thesis demonstrates this and thus marks an important step towards targeted therapy for MC1.

Abstract

The thesis investigates the pathobiology of Modic changes (MCs), specifically focusing on Modic type 1 changes (MC1), emphasizing the complexity of the disease. Although MCs manifest as vertebral bone marrow lesions, the inflammation and degeneration observed in the neighboring intervertebral disc and cartilage endplate (CEP) are also closely linked to MCs. However, the underlying mechanisms and how the tissues crosstalk to induce MC development are unclear to this point. Yet, comprehending these pathobiological mechanisms is crucial for the development of targeted therapies, which are currently nonexistent. The thesis explores various aspects of MC1 addressing pathologic processes seen within the MC1 bone marrow, the CEP and the disc. Finally, the project's findings suggest a new disease mechanism for MC1 development initiated through MC1 specific disc degeneration.

Chapter three investigated the impact of bone marrow stromal cells (BMSC) from MC1 on neurite outgrowth, using an in-vitro co-culture system. Multiple studies have reported an elevated presence of nerve fibers in the MC1 bone marrow and endplate, a definitive connection to the underlying cause has not been established. For the first time, the dysregulated MC1 BMSCs were directly linked to increased neurite outgrowth. With this knowledge, an important treatment target has been identified, paving the way for further studies to explore how to mitigate this effect.

The fourth chapter explores the concept of a disc microbiome, particularly focusing on the MC1 and MC2 microbiomes, using metagenomic analysis. The disc microbiome challenges the conventional notion of disc sterility, necessitating clear methodological definitions for further investigation. Although our analysis confirmed the presence of a disc microbiome, the findings deviated from those of previous studies on degenerated MC discs, even after aligning the parameters of bioinformatic analysis to the previous studies. This study underscores the importance of not only standardizing bioinformatic analysis approaches but also further investigating factors that influence the bacterial composition of the disc microbiome. Differences could stem from sample preparation techniques or variations in the geographical and ethnic backgrounds of patients. Once clarified, the exploration of the disc microbiome will unlock numerous opportunities for diagnostic and treatment applications.

The fifth chapter of the thesis highlights the to this point overlooked biological role of CEP cells. The experiments were able to confirm the presence of Toll-like receptors (TLRs) on CEP cells and particularly emphasized the presence of TLR2 as it was the only TLR that was upregulated through direct stimulation. The discovery of TLRs on CEP cells is noteworthy due to their high density compared to the cells in the adjacent disc and their ability to induce inflammation and promote the production of catabolic enzymes, potentially leading to endplate degeneration. This not only enhances our understanding of CEP cells but also reveals novel treatment targets.

The sixth chapter presents the main project of the thesis, which focuses on understanding MC1 pathobiology and proposes a new mechanism for MC1 development beginning with MC1-specific disc degeneration. It is grounded in the fact that although disc degeneration is often observed in the disc adjacent to MC1, not all degenerated discs progress to MC1. The proposed MC1-specific disc degeneration is hypothesized to generate more fragments, triggering inflammation in the adjacent endplate, causing endplate destruction. This ultimately breaches the CEP barrier between the disc and bone marrow, allowing pro-inflammatory fragments (damage associated molecular patterns (DAMPs)) and inflammatory cytokines to spill over into the bone marrow, inducing MC1. Although the study is ongoing, significant discoveries have been made. MC1 discs were found to have a higher abundance of extracellular matrix derived fragments as well a greater abundance of the protease high temperature requirement serine protease 1 (HTRA1) than degenerated nonMC discs. In a subsequent phase, the abundant cartilage intermediate layer protein 1 (CILP1) fragments were successfully replicated by exposure to HTRA1 and were demonstrated to possess pro-inflammatory properties via TLR4 signaling activation, thereby classifying them as DAMPs. A CEP explant model was used to show that TLR activation can induce CEP tissue destruction, connecting the DAMP abundance in the disc to CEP damage. However, further experiments are necessary to address the gaps within the proposed mechanism.

MC1 is a pathology associated with distinct inflammatory and pain-related processes, suggesting it could and should be treated specifically. This thesis demonstrates this and thus marks an important step towards targeted therapy for MC1.

Statistics

Downloads

22 downloads since deposited on 17 Jun 2024
22 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Dissertation (monographical)
Referees:Distler Oliver, Dudli Stefan, Grad Sibylle, Stockmann Christian
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

07 Faculty of Science > Institute of Molecular Life Sciences
05 Vetsuisse Faculty > Veterinärwissenschaftliches Institut > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease

UZH Dissertations
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Language:English
Place of Publication:Zürich
Date:17 June 2024
Deposited On:17 Jun 2024 12:02
Last Modified:17 Jun 2024 12:02
Number of Pages:134
OA Status:Green
  • Content: Published Version
  • Language: English