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The Role of Extracellular Matrix Proteins in Pathogenesis
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The Role of Extracellular Matrix Proteins in Pathogenesis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 11345

Special Issue Editor

Dr. Davide Raineri

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Guest Editor
Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy
Interests: osteopontin; cancers; autoimmune diseases; inflammation; chronic diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extracellular matrix (ECM) proteins play a crucial role in the pathogenesis of various diseases by contributing to tissue remodeling, cell signaling, and immune response modulation. The ECM is a complex network of proteins and other molecules that provides structural support and regulates cell behavior in tissues. In the context of disease pathogenesis, ECM proteins play crucial roles in various pathological processes. One of the key functions of ECM proteins is to maintain tissue integrity and architecture. Disruption or dysregulation of ECM proteins can lead to tissue remodeling, fibrosis, and impaired organ function. For example, in diseases like pulmonary fibrosis or liver cirrhosis, excessive deposition of ECM proteins, particularly collagens, disrupts the normal tissue architecture, resulting in organ dysfunction. Moreover, ECM proteins serve as signaling molecules and interact with cell surface receptors to modulate cellular behavior. A class of ECM receptors called integrins is essential for cell adhesion, migration, and proliferation. Dysregulation of ECM–integrin interactions can contribute to the progression of cancer by promoting tumor cell invasion and metastasis. ECM proteins are also involved in inflammatory disorders like autoimmune disease. In conditions such as rheumatoid arthritis, inflammatory cells release enzymes called matrix metalloproteinases (MMPs), which degrade ECM proteins, leading to joint destruction and tissue damage. In contrast, excessive ECM protein deposition in chronic inflammatory diseases like atherosclerosis can cause plaque development and arterial stiffness. In summary, ECM proteins play multifaceted roles in disease pathogenesis. Their dysregulation disrupts tissue homeostasis, promotes inflammation, facilitates tumor progression, and contributes to fibrosis and cardiovascular disorders. Understanding the complex interplay between ECM proteins and disease processes is crucial for developing therapeutic strategies that target the ECM to alleviate disease progression and improve patient outcomes.

This Special Issue aims to bring together research articles and reviews that help to understand those still unknown molecular mechanisms of ECM proteins in the pathogenesis of diseases.

Dr. Davide Raineri
Guest Editor

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Keywords

  • extracellular matrix proteins
  • autoimmune disease
  • cancer
  • cardiovascular diseases
  • inflammation
  • chronic diseases
  • human diseases

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Published Papers (8 papers)

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Research

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21 pages, 4837 KiB  
Article
Extracellular Microenvironment Alterations in Ductal Carcinoma In Situ and Invasive Breast Cancer Pathologies by Multiplexed Spatial Proteomics
by Taylor S. Hulahan, Laura Spruill, Elizabeth N. Wallace, Yeonhee Park, Robert B. West, Jeffrey R. Marks, E. Shelley Hwang, Richard R. Drake and Peggi M. Angel
Int. J. Mol. Sci. 2024, 25(12), 6748; https://doi.org/10.3390/ijms25126748 - 19 Jun 2024
Viewed by 1115
Abstract
Ductal carcinoma in situ (DCIS) is a heterogeneous breast disease that remains challenging to treat due to its unpredictable progression to invasive breast cancer (IBC). Contemporary literature has become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial [...] Read more.
Ductal carcinoma in situ (DCIS) is a heterogeneous breast disease that remains challenging to treat due to its unpredictable progression to invasive breast cancer (IBC). Contemporary literature has become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial regulation of the ECM proteome in DCIS has yet to be investigated in relation to IBC. We hypothesized that DCIS and IBC present distinct ECM proteomes that could discriminate between these pathologies. Tissue sections of pure DCIS, mixed DCIS-IBC, or pure IBC (n = 22) with detailed pathological annotations were investigated by multiplexed spatial proteomics. Across tissues, 1,005 ECM peptides were detected in pathologically annotated regions and their surrounding extracellular microenvironments. A comparison of DCIS to IBC pathologies demonstrated 43 significantly altered ECM peptides. Notably, eight fibrillar collagen peptides could distinguish with high specificity and sensitivity between DCIS and IBC. Lesion-targeted proteomic imaging revealed heterogeneity of the ECM proteome surrounding individual DCIS lesions. Multiplexed spatial proteomics reported an invasive cancer field effect, in which DCIS lesions in closer proximity to IBC shared a more similar ECM profile to IBC than distal counterparts. Defining the ECM proteomic microenvironment provides novel molecular insights relating to DCIS and IBC. Full article
(This article belongs to the Special Issue The Role of Extracellular Matrix Proteins in Pathogenesis)
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20 pages, 3088 KiB  
Article
Early Stages of Ex Vivo Collagen Glycation Disrupt the Cellular Interaction and Its Remodeling by Mesenchymal Stem Cells—Morphological and Biochemical Evidence
by Regina Komsa-Penkova, Borislav Dimitrov, Svetla Todinova, Violina Ivanova, Svetoslava Stoycheva, Peter Temnishki, Galya Georgieva, Pencho Tonchev, Mario Iliev and George Altankov
Int. J. Mol. Sci. 2024, 25(11), 5795; https://doi.org/10.3390/ijms25115795 - 26 May 2024
Viewed by 1044
Abstract
Mesenchymal stem cells (MSCs), pivotal for tissue repair, utilize collagen to restore structural integrity in damaged tissue, preserving its organization through concomitant remodeling. The non-enzymatic glycation of collagen potentially compromises MSC communication, particularly upon advancing the process, underlying various pathologies such as late-stage [...] Read more.
Mesenchymal stem cells (MSCs), pivotal for tissue repair, utilize collagen to restore structural integrity in damaged tissue, preserving its organization through concomitant remodeling. The non-enzymatic glycation of collagen potentially compromises MSC communication, particularly upon advancing the process, underlying various pathologies such as late-stage diabetic complications and aging. However, an understanding of the impact of early-stage collagen glycation on MSC interaction is lacking. This study examines the fate of in vitro glycated rat tail collagen (RTC) upon exposure to glucose for 1 or 5 days in contact with MSCs. Utilizing human adipose tissue-derived MSCs (ADMSCs), we demonstrate their significantly altered interaction with glycated collagen, characterized morphologically by reduced cell spreading, diminished focal adhesions formation, and attenuated development of the actin cytoskeleton. The morphological findings were confirmed by ImageJ 1.54g morphometric analysis with the most significant drop in the cell spreading area (CSA), from 246.8 μm2 for the native collagen to 216.8 μm2 and 163.7 μm2 for glycated ones, for 1 day and 5 days, respectively, and a similar trend was observed for cell perimeter 112.9 μm vs. 95.1 μm and 86.2 μm, respectively. These data suggest impaired recognition of early glycated collagen by integrin receptors. Moreover, they coincide with the reduced fibril-like reorganization of adsorbed FITC-collagen (indicating impaired remodeling) and a presumed decreased sensitivity to proteases. Indeed, confirmatory assays reveal diminished FITC-collagen degradation for glycated samples at 1 day and 5 days by attached cells (22.8 and 30.4%) and reduced proteolysis upon exogenous collagenase addition (24.5 and 40.4%) in a cell-free system, respectively. The mechanisms behind these effects remain uncertain, although differential scanning calorimetry confirms subtle structural/thermodynamic changes in glycated collagen. Full article
(This article belongs to the Special Issue The Role of Extracellular Matrix Proteins in Pathogenesis)
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17 pages, 4393 KiB  
Article
The Effects of Chronic Immunosuppressive Treatment on Morphological Changes in Cardiac Tissue and the Balance between Matrix Metalloproteinases (MMP-2 and MMP-9) and Their Inhibitors in the Rat Heart
by Anna Surówka, Michał Żołnierczuk, Piotr Prowans, Marta Grabowska, Patrycja Kupnicka, Marta Markowska, Joanna Olejnik-Wojciechowska, Zbigniew Szlosser, Aleksandra Wilk, Kamila Szumilas and Karolina Kędzierska-Kapuza
Int. J. Mol. Sci. 2024, 25(8), 4468; https://doi.org/10.3390/ijms25084468 - 18 Apr 2024
Cited by 1 | Viewed by 1138
Abstract
Using different three-drug immunosuppressive treatment regimens in a rat model, we aimed to determine the effects of long-term therapy on metalloproteinase-2 and metalloproteinase-9 activity and the expression of their inhibitors, as well as to assess the morphology of the animals’ cardiac tissue. Our [...] Read more.
Using different three-drug immunosuppressive treatment regimens in a rat model, we aimed to determine the effects of long-term therapy on metalloproteinase-2 and metalloproteinase-9 activity and the expression of their inhibitors, as well as to assess the morphology of the animals’ cardiac tissue. Our results suggest that chronic use of immunosuppressive drugs disrupts the balance between the activity of MMPs and TIMPs. Depending on the type of drug regimen used, this leads to abnormalities in the cardiac structure, collagen fiber accumulation, or cardiomyocyte hypertrophy. The information obtained in the present study allows us to conclude that the chronic treatment of rats with the most common clinical immunosuppressive regimens may contribute to abnormalities in the myocardial structure and function. The results presented in this study may serve as a prelude to more in-depth analyses and additional research into the optimal selection of an immunosuppressive treatment with the lowest possible risk of cardiovascular complications for patients receiving organ transplants. Full article
(This article belongs to the Special Issue The Role of Extracellular Matrix Proteins in Pathogenesis)
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15 pages, 9055 KiB  
Article
Lung Inflammatory Phenotype in Mice Deficient in Fibulin-2 and ADAMTS-12
by Yamina Mohamedi, Tania Fontanil, José A. Vega, Teresa Cobo, Santiago Cal and Álvaro J. Obaya
Int. J. Mol. Sci. 2024, 25(4), 2024; https://doi.org/10.3390/ijms25042024 - 7 Feb 2024
Viewed by 1214
Abstract
Interaction between extracellular matrix (ECM) components plays an important role in the regulation of cellular behavior and hence in tissue function. Consequently, characterization of new interactions within ECM opens the possibility of studying not only the functional but also the pathological consequences derived [...] Read more.
Interaction between extracellular matrix (ECM) components plays an important role in the regulation of cellular behavior and hence in tissue function. Consequently, characterization of new interactions within ECM opens the possibility of studying not only the functional but also the pathological consequences derived from those interactions. We have previously described the interaction between fibulin2 and ADAMTS-12 in vitro and the effects of that interaction using cellular models of cancer. Now, we generate a mouse deficient in both ECM components and evaluate functional consequences of their absence using different cancer and inflammation murine models. The main findings indicate that mice deficient in both fibulin2 and ADAMTS12 markedly increase the development of lung tumors following intraperitoneal urethane injections. Moreover, inflammatory phenotype is exacerbated in the lung after LPS treatment as can be inferred from the accumulation of active immune cells in lung parenchyma. Overall, our results suggest that protective effects in cancer or inflammation shown by fibulin2 and ADAMTS12 as interactive partners in vitro are also shown in a more realistic in vivo context. Full article
(This article belongs to the Special Issue The Role of Extracellular Matrix Proteins in Pathogenesis)
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14 pages, 4626 KiB  
Article
Differential Proteoglycan Expression in Atherosclerosis Alters Platelet Adhesion and Activation
by Amelia Drysdale, Maria Blanco-Lopez, Stephen J. White, Amanda J. Unsworth and Sarah Jones
Int. J. Mol. Sci. 2024, 25(2), 950; https://doi.org/10.3390/ijms25020950 - 12 Jan 2024
Viewed by 1608
Abstract
Proteoglycans are differentially expressed in different atherosclerotic plaque phenotypes, with biglycan and decorin characteristic of ruptured plaques and versican and hyaluronan more prominent in eroded plaques. Following plaque disruption, the exposure of extracellular matrix (ECM) proteins triggers platelet adhesion and thrombus formation. In [...] Read more.
Proteoglycans are differentially expressed in different atherosclerotic plaque phenotypes, with biglycan and decorin characteristic of ruptured plaques and versican and hyaluronan more prominent in eroded plaques. Following plaque disruption, the exposure of extracellular matrix (ECM) proteins triggers platelet adhesion and thrombus formation. In this study, the impact of differential plaque composition on platelet function and thrombus formation was investigated. Platelet adhesion, activation and thrombus formation under different shear stress conditions were assessed in response to individual proteoglycans and composites representing different plaque phenotypes. The results demonstrated that all the proteoglycans tested mediated platelet adhesion but not platelet activation, and the extent of adhesion observed was significantly lower than that observed with type I and type III collagens. Thrombus formation upon the rupture and erosion ECM composites was significantly reduced (p < 0.05) compared to relevant collagen alone, indicating that proteoglycans negatively regulate platelet collagen responses. This was supported by results demonstrating that the addition of soluble biglycan or decorin to whole blood markedly reduced thrombus formation on type I collagen (p < 0.05). Interestingly, thrombus formation upon the erosion composite displayed aspirin sensitivity, whereas the rupture composite was intensive to aspirin, having implications for current antiplatelet therapy regimes. In conclusion, differential platelet responses and antiplatelet efficacy are observed on ECM composites phenotypic of plaque rupture and erosion. Proteoglycans inhibit thrombus formation and may offer a novel plaque-specific approach to limit arterial thrombosis. Full article
(This article belongs to the Special Issue The Role of Extracellular Matrix Proteins in Pathogenesis)
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Review

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10 pages, 1325 KiB  
Review
An Eye into the Aorta: The Role of Extracellular Matrix Regulatory Genes ZNF469 and PRDM5, from Their Previous Association with Brittle Cornea Syndrome to Their Novel Association with Aortic and Arterial Aneurysmal Diseases
by Peyton Moore, Adam Wolf and Mohanakrishnan Sathyamoorthy
Int. J. Mol. Sci. 2024, 25(11), 5848; https://doi.org/10.3390/ijms25115848 - 28 May 2024
Viewed by 1162
Abstract
The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been [...] Read more.
The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes’ development of aneurysmal and dissection diseases. Full article
(This article belongs to the Special Issue The Role of Extracellular Matrix Proteins in Pathogenesis)
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16 pages, 1425 KiB  
Review
The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves’ Ophthalmopathy
by Hsun-I Chiu, Shi-Bei Wu and Chieh-Chih Tsai
Int. J. Mol. Sci. 2024, 25(6), 3288; https://doi.org/10.3390/ijms25063288 - 14 Mar 2024
Cited by 3 | Viewed by 1751
Abstract
Graves’ ophthalmopathy (GO), or thyroid eye disease (TED), is the most frequent extrathyroidal manifestation of Graves’ disease (GD). Inflammation and subsequent aberrant tissue remodeling with fibrosis are important pathogenesis. There are many proposed mechanisms and molecular pathways contributing to tissue remodeling and fibrosis [...] Read more.
Graves’ ophthalmopathy (GO), or thyroid eye disease (TED), is the most frequent extrathyroidal manifestation of Graves’ disease (GD). Inflammation and subsequent aberrant tissue remodeling with fibrosis are important pathogenesis. There are many proposed mechanisms and molecular pathways contributing to tissue remodeling and fibrosis in GO, including adipogenesis, fibroblast proliferation and myofibroblasts differentiation, oxidative stress, endoplasmic reticulum (ER) stress, hyaluronan (HA) and glycosaminoglycans (GAGs) accumulation in the extracellular matrix (ECM) and new concepts of epigenetics modification, such as histone modification, DNA methylation, non-coding RNAs, and gut microbiome. This review summarizes the current understanding of ECM proteins and associated tissue remodeling in the pathogenesis and potential mediators for the treatment of GO. Full article
(This article belongs to the Special Issue The Role of Extracellular Matrix Proteins in Pathogenesis)
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13 pages, 811 KiB  
Review
Matrix Metalloproteinases and Their Inhibitors as Potential Prognostic Biomarkers in Head and Neck Cancer after Radiotherapy
by Gabriel Fornieles, María Isabel Núñez and José Expósito
Int. J. Mol. Sci. 2024, 25(1), 527; https://doi.org/10.3390/ijms25010527 - 30 Dec 2023
Cited by 2 | Viewed by 1314
Abstract
Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour. HNC is traditionally known as head and neck squamous cell carcinoma (HNSCC), since [...] Read more.
Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour. HNC is traditionally known as head and neck squamous cell carcinoma (HNSCC), since 90% arises from epithelial cells. Metastasis remains a major cause of mortality in patients with HNSCC. HNSCC patients with metastatic disease have an extremely poor prognosis with a survival rate of less than a year. Matrix metalloproteinases (MMPs) have been described as biomarkers that promote cell migration and invasion. Radiotherapy is widely used to treat HNSCC, being a determining factor in the alteration of the tumour’s biology and microenvironment. This review focuses on analysing the current state of the scientific literature on this topic. Although few studies have focused on the role of these proteinases in HNC, some authors have concluded that radiotherapy alters the behaviour of MMPs and tissue inhibitors of metalloproteinases (TIMPs). Therefore, more research is needed to understand the roles played by MMPs and their inhibitors (TIMPs) as prognostic biomarkers in patients with HNC and their involvement in the response to radiotherapy. Full article
(This article belongs to the Special Issue The Role of Extracellular Matrix Proteins in Pathogenesis)
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