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Extracellular Matrix in Development and Disease 4.0

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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 October 2023) | Viewed by 12617

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Prof. Dr. Frank Zaucke

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Research Unit for Osteoarthritis, Department of Orthopaedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, Marienburgstraße 2, 60528 Frankfurt/Main, Germany
Interests: extracellular matrix proteins; collagens; cartilage; bone; skeletal development; mouse models; chondrodysplasias; osteoarthritis; chondrogenesis; chondrocyte differentiation; skin homeostasis
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issues, “Extracellular Matrix in Development and Disease” (https://www.mdpi.com/journal/ijms/special_issues/extracellular_matrix), "Extracellular Matrix in Development and Disease 2.0" (https://www.mdpi.com/journal/ijms/special_issues/extracellular_matrix2), and "Extracellular Matrix in Development and Disease 3.0" (https://www.mdpi.com/journal/ijms/special_issues/extracellular_matrix3).

This Special Issue, “Extracellular Matrix in Development and Disease 4.0", will deal with molecular and cellular aspects of the role of the extracellular matrix in development and disease. Cells exist in a three-dimensional scaffold called the extracellular matrix. The matrix holds together the millions of cells that make up our blood vessels, organs, skin, and all tissues of the body. The matrix also serves as a reservoir of signaling molecules. In bacterial cultures, biofilms form as an extracellular matrix and play essential roles in disease and drug resistance. Topics such as matrix structure and function, cell attachment, and cell surface proteins that mediate cell–matrix interactions as well as the synthesis, regulation, composition, structure, assembly, remodeling, and function of the matrix are included.

A common thread uniting the topics is the essential nature that the matrix plays in normal development and pathophysiology. Providing new knowledge will lead us to improved diagnostics, preventions of disease progression, and therapeutic strategies for the repair and regeneration of tissues.

Prof. Dr. Frank Zaucke
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

extracellular matrix
collagen
biofilm
embryonic development
degenerative disease
fibrosis
tissue engineering

Published Papers (7 papers)

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Research

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16 pages, 4784 KiB

Open AccessArticle

LRG1 Promotes ECM Integrity by Activating the TGF-β Signaling Pathway in Fibroblasts

by Han Na Park, Min Ji Song, Young Eun Choi, Dong Hun Lee, Jin Ho Chung and Seung-Taek Lee

Int. J. Mol. Sci. 2023, 24(15), 12445; https://doi.org/10.3390/ijms241512445 - 4 Aug 2023

Cited by 4 | Viewed by 1461

Abstract

Leucine-rich alpha-2-glycoprotein 1 (LRG1) mediates skin repair and fibrosis by stimulating the transforming growth factor-beta (TGF-β) signaling pathway. In the present study, we investigated the effect of LRG1 on extracellular matrix (ECM) integrity in fibroblasts, as well as on skin aging. The treatment of dermal fibroblasts with purified recombinant human LRG1 increased type I collagen secretion and decreased matrix metalloproteinase-1 secretion. Additionally, LRG1 promoted SMAD2/SMAD3 phosphorylation in a pattern similar to that of TGF-β1 treatment. An inhibitor of TGF-β receptor 1 abolished LRG1-induced SMAD2 phosphorylation. RNA sequencing identified “extracellular region”, “extracellular space”, and “extracellular matrix” as the main Gene Ontology terms in the differentially expressed genes of fibroblasts treated with or without LRG1. LRG1 increased TGF-β1 mRNA levels, suggesting that LRG1 partially transactivates the expression of TGF-β1. Furthermore, an increased expression of type I collagen was also observed in fibroblasts grown in three-dimensional cultures on a collagen gel mimicking the dermis. LRG1 mRNA and protein levels were significantly reduced in elderly human skin tissues with weakened ECM integrity compared to in young human skin tissues. Taken together, our results suggest that LRG1 could retard skin aging by activating the TGF-β signaling pathway, increasing ECM deposition while decreasing its degradation. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 4.0)

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12 pages, 4409 KiB

Open AccessArticle

Sortilin Is Upregulated in Osteoarthritis-Dependent Cartilage Calcification and Associated with Cellular Senescence

by Elisabeth Richter, Christoph H. Lohmann, Francesco Dell’Accio, Claudia Goettsch and Jessica Bertrand

Int. J. Mol. Sci. 2023, 24(15), 12343; https://doi.org/10.3390/ijms241512343 - 2 Aug 2023

Cited by 2 | Viewed by 1079

Abstract

Osteoarthritis (OA) is a chronic joint disease characterized by articular cartilage calcification, loss of articular cartilage, bone changes, pain, and disability. Cartilage calcification is one hallmark of OA and is predominantly caused by basic calcium crystals formed due to an imbalance of the pyrophosphate pathway. Sortilin is a transmembrane protein that contributes to vascular calcification in atherosclerosis by externalizing alkaline phosphatase (ALP)-containing vesicles. Calcification in atherosclerosis and osteoarthritis has been associated with cellular senescence. The aim of this study was to investigate the potential role of sortilin and senescence in osteoarthritis-dependent cartilage calcification. Osteoarthritic cartilage from human knee joints was collected after joint replacement, and samples were analyzed by immunohistochemistry and quantitative RT-PCR analysis. Human chondrocytes were treated with osteogenic medium for up to 21 days to induce calcification. Western blots for sortilin and ALP, as well as an ALP activity assay, were performed. Human chondrocytes were treated with mitomycin C to induce senescence, and sortilin expression was quantified at the protein and gene levels. Sections of knee joints from a murine model of osteoarthritis were stained for sortilin and p16 and analyzed by immunohistochemistry. Treatment of wild-type chondrocytes using an osteogenic medium similar to human chondrocytes was performed. Osteoarthritic cartilage from mouse and human knee joints showed an increased number of sortilin and p16-positive chondrocytes compared to healthy cartilage. This observation was corroborated by increased gene expression of sortilin and p16 in mild and moderate osteoarthritic cartilage samples. To investigate the mechanism of sortilin regulation, human chondrocytes were treated with osteogenic medium to induce calcification. Sortilin protein levels and expression were increased after 7 days of stimulation, whereas ALP levels and activity were upregulated after 21 days of stimulation. Similar observations were made in a murine osteoarthritis model. Mechanistically, senescent chondrocytes induced by mitomycin C showed an upregulation of sortilin and ALP gene expression compared to non-senescent chondrocytes. Our data indicate that sortilin and ALP are upregulated during cartilage calcification, which is associated with chondrocyte senescence and thus might contribute to the pathogenesis of osteoarthritis. Cellular senescence seems to induce sortilin expression. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 4.0)

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14 pages, 3546 KiB

Open AccessArticle

SPARC Is Highly Expressed in Young Skin and Promotes Extracellular Matrix Integrity in Fibroblasts via the TGF-β Signaling Pathway

by Seung Min Ham, Min Ji Song, Hyun-Sun Yoon, Dong Hun Lee, Jin Ho Chung and Seung-Taek Lee

Int. J. Mol. Sci. 2023, 24(15), 12179; https://doi.org/10.3390/ijms241512179 - 29 Jul 2023

Cited by 3 | Viewed by 1429

Abstract

The matricellular secreted protein acidic and rich in cysteine (SPARC; also known as osteonectin), is involved in the regulation of extracellular matrix (ECM) synthesis, cell-ECM interactions, and bone mineralization. We found decreased SPARC expression in aged skin. Incubating foreskin fibroblasts with recombinant human SPARC led to increased type I collagen production and decreased matrix metalloproteinase-1 (MMP-1) secretion at the protein and mRNA levels. In a three-dimensional culture of foreskin fibroblasts mimicking the dermis, SPARC significantly increased the synthesis of type I collagen and decreased its degradation. In addition, SPARC also induced receptor-regulated SMAD (R-SMAD) phosphorylation. An inhibitor of transforming growth factor-beta (TGF-β) receptor type 1 reversed the SPARC-induced increase in type I collagen and decrease in MMP-1, and decreased SPARC-induced R-SMAD phosphorylation. Transcriptome analysis revealed that SPARC modulated expression of genes involved in ECM synthesis and regulation in fibroblasts. RT-qPCR confirmed that a subset of differentially expressed genes is induced by SPARC. These results indicated that SPARC enhanced ECM integrity by activating the TGF-β signaling pathway in fibroblasts. We inferred that the decline in SPARC expression in aged skin contributes to process of skin aging by negatively affecting ECM integrity in fibroblasts. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 4.0)

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15 pages, 3904 KiB

Open AccessArticle

The Fraser Complex Proteins (Frem1, Frem2, and Fras1) Can Form Anchoring Cords in the Absence of AMACO at the Dermal–Epidermal Junction of Mouse Skin

by Temitope Esho, Birgit Kobbe, Sara F. Tufa, Douglas R. Keene, Mats Paulsson and Raimund Wagener

Int. J. Mol. Sci. 2023, 24(7), 6782; https://doi.org/10.3390/ijms24076782 - 5 Apr 2023

Cited by 1 | Viewed by 1260

Abstract

AMACO (VWA2 protein), secreted by epithelial cells, is strongly expressed at basement membranes when budding or invagination occurs in embryos. In skin, AMACO associates with proteins of the Fraser complex, which form anchoring cords. These, during development, temporally stabilize the dermal–epidermal junction, pending the formation of collagen VII-containing anchoring fibrils. Fraser syndrome in humans results if any of the core members of the Fraser complex (Fras1, Frem1, Frem2) are mutated. Fraser syndrome is characterized by subepidermal blistering, cryptophthalmos, and syndactyly. In an attempt to determine AMACO function, we generated and characterized AMACO-deficient mice. In contrast to Fraser complex mutant mice, AMACO-deficient animals lack an obvious phenotype. The mutually interdependent basement membrane deposition of the Fraser complex proteins, and the formation of anchoring cords, are not affected. Furthermore, hair follicle development in newborn AMACO-deficient mice showed no gross aberration. Surprisingly, it appears that, while AMACO is a component of the anchoring cords, it is not essential for their formation or function. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 4.0)

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Review

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22 pages, 2756 KiB

Open AccessReview

Proteins and Transcriptional Dysregulation of the Brain Extracellular Matrix in Parkinson’s Disease: A Systematic Review

by Wote Amelo Rike and Shani Stern

Int. J. Mol. Sci. 2023, 24(8), 7435; https://doi.org/10.3390/ijms24087435 - 18 Apr 2023

Cited by 7 | Viewed by 1874

Abstract

The extracellular matrix (ECM) of the brain is a dynamic structure made up of a vast network of bioactive macromolecules that modulate cellular events. Structural, organizational, and functional changes in these macromolecules due to genetic variation or environmental stressors are thought to affect cellular functions and may result in disease. However, most mechanistic studies to date usually focus on the cellular aspects of diseases and pay less attention to the relevance of the processes governing the dynamic nature of the extracellular matrix in disease pathogenesis. Thus, due to the ECM’s diversified biological roles, increasing interest in its involvement in disease, and the lack of sufficient compiled evidence regarding its relationship with Parkinson’s disease (PD) pathology, we aimed to compile the existing evidence to boost the current knowledge on the area and provide refined guidance for the future research. Here, in this review, we gathered postmortem brain tissue and induced pluripotent stem cell (iPSC)-related studies from PubMed and Google Scholar to identify, summarize and describe common macromolecular alterations in the expression of brain ECM components in Parkinson’s disease (PD). A literature search was conducted up until 10 February 2023. The overall hits from the database and manual search for proteomic and transcriptome studies were 1243 and 1041 articles, respectively. Following a full-text review, 10 articles from proteomic and 24 from transcriptomic studies were found to be eligible for inclusion. According to proteomic studies, proteins such as collagens, fibronectin, annexins, and tenascins were recognized to be differentially expressed in Parkinson’s disease. Transcriptomic studies displayed dysregulated pathways including ECM–receptor interaction, focal adhesion, and cell adhesion molecules in Parkinson’s disease. A limited number of relevant studies were accessed from our search, indicating that much work remains to be carried out to better understand the roles of the ECM in neurodegeneration and Parkinson’s disease. However, we believe that our review will elicit focused primary studies and thus support the ongoing efforts of the discovery and development of diagnostic biomarkers as well as therapeutic agents for Parkinson’s disease. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 4.0)

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17 pages, 3899 KiB

Open AccessReview

Advances in Cartilage Tissue Engineering Using Bioinks with Decellularized Cartilage and Three-Dimensional Printing

by Roxanne N. Stone, Jonathon C. Reeck and Julia Thom Oxford

Int. J. Mol. Sci. 2023, 24(6), 5526; https://doi.org/10.3390/ijms24065526 - 14 Mar 2023

Cited by 5 | Viewed by 2121

Abstract

Osteoarthritis, a chronic, debilitating, and painful disease, is one of the leading causes of disability and socioeconomic burden, with an estimated 250 million people affected worldwide. Currently, there is no cure for osteoarthritis and treatments for joint disease require improvements. To address the challenge of improving cartilage repair and regeneration, three-dimensional (3D) printing for tissue engineering purposes has been developed. In this review, emerging technologies are presented with an overview of bioprinting, cartilage structure, current treatment options, decellularization, bioinks, and recent progress in the field of decellularized extracellular matrix (dECM)–bioink composites is discussed. The optimization of tissue engineering approaches using 3D-bioprinted biological scaffolds with dECM incorporated to create novel bioinks is an innovative strategy to promote cartilage repair and regeneration. Challenges and future directions that may lead to innovative improvements to currently available treatments for cartilage regeneration are presented. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 4.0)

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21 pages, 1799 KiB

Open AccessReview

Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation

by Nunzia Mollo, Roberta Scognamiglio, Anna Conti, Simona Paladino, Lucio Nitsch and Antonella Izzo

Int. J. Mol. Sci. 2023, 24(3), 2918; https://doi.org/10.3390/ijms24032918 - 2 Feb 2023

Cited by 3 | Viewed by 2667

Abstract

Down syndrome (DS), a complex disorder that is caused by the trisomy of chromosome 21 (Hsa21), is a major cause of congenital heart defects (CHD). Interestingly, only about 50% of individuals with Hsa21 trisomy manifest CHD. Here we review the genetic basis of CHD in DS, focusing on genes that regulate extracellular matrix (ECM) organization. The overexpression of Hsa21 genes likely underlies the molecular mechanisms that contribute to CHD, even though the genes responsible for CHD could only be located in a critical region of Hsa21. A role in causing CHD has been attributed not only to protein-coding Hsa21 genes, but also to genes on other chromosomes, as well as miRNAs and lncRNAs. It is likely that the contribution of more than one gene is required, and that the overexpression of Hsa21 genes acts in combination with other genetic events, such as specific mutations or polymorphisms, amplifying their effect. Moreover, a key function in determining alterations in cardiac morphogenesis might be played by ECM. A large number of genes encoding ECM proteins are overexpressed in trisomic human fetal hearts, and many of them appear to be under the control of a Hsa21 gene, the RUNX1 transcription factor. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 4.0)

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