Genetic Disorders of the Extracellular Matrix

Lamandé, Shireen R.; Bateman, John F.

doi:10.1002/ar.24086

Cited by 61 publications

(44 citation statements)

References 129 publications

(163 reference statements)

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“…In fibrotic conditions, increased ECM production, accumulation of ECM fragments, augmented secretion of cytokines, fibroblast-to-myofibroblast transition, and activation of immune responses, dependent on toll-like receptors, occur [26]. The regulation of ECM synthesis and remodeling is central for human health, as recognized in different heritable connective tissue disorders [1,27]. Indeed, molecular defects in a large range of ECM-related genes, including those encoding enzymes involved in biosynthesis or processing of ECM proteins, cause a myriad of connective tissue disorders, e.g., Ehlers–Danlos syndromes, Osteogenesis imperfecta, Marfan syndrome, Loeys–Dietz syndromes, arterial tortuosity syndrome, and numerous skeletal dysplasias [1,27].…”

Section: Pathological Ecm Remodeling and Perturbation Of Cellular mentioning

confidence: 99%

“…The regulation of ECM synthesis and remodeling is central for human health, as recognized in different heritable connective tissue disorders [1,27]. Indeed, molecular defects in a large range of ECM-related genes, including those encoding enzymes involved in biosynthesis or processing of ECM proteins, cause a myriad of connective tissue disorders, e.g., Ehlers–Danlos syndromes, Osteogenesis imperfecta, Marfan syndrome, Loeys–Dietz syndromes, arterial tortuosity syndrome, and numerous skeletal dysplasias [1,27]. These disorders are characterized by a multisystem involvement in terms of cardiovascular, skeletal, and cutaneous features [28], highlighting the functional relevance of the ECM in ensuring the integrity and function of several connective tissues.…”

Section: Pathological Ecm Remodeling and Perturbation Of Cellular mentioning

confidence: 99%

“…The pathological consequences of defects in ECM components depend on the balance between extracellular effects, e.g., reduced protein secretion and export of misfolded proteins, and intracellular consequences such as apoptosis activation, ER dysfunction, and autophagy perturbation that impact in different ways on the molecular pathology and disease severity [27,29,30,31].…”

Section: Pathological Ecm Remodeling and Perturbation Of Cellular mentioning

confidence: 99%

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Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

Chiarelli

Ritelli

Zoppi

et al. 2019

Genes

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The Ehlers‒Danlos syndromes (EDS) constitute a heterogenous group of connective tissue disorders characterized by joint hypermobility, skin abnormalities, and vascular fragility. The latest nosology recognizes 13 types caused by pathogenic variants in genes encoding collagens and other molecules involved in collagen processing and extracellular matrix (ECM) biology. Classical (cEDS), vascular (vEDS), and hypermobile (hEDS) EDS are the most frequent types. cEDS and vEDS are caused respectively by defects in collagen V and collagen III, whereas the molecular basis of hEDS is unknown. For these disorders, the molecular pathology remains poorly studied. Herein, we review, expand, and compare our previous transcriptome and protein studies on dermal fibroblasts from cEDS, vEDS, and hEDS patients, offering insights and perspectives in their molecular mechanisms. These cells, though sharing a pathological ECM remodeling, show differences in the underlying pathomechanisms. In cEDS and vEDS fibroblasts, key processes such as collagen biosynthesis/processing, protein folding quality control, endoplasmic reticulum homeostasis, autophagy, and wound healing are perturbed. In hEDS cells, gene expression changes related to cell-matrix interactions, inflammatory/pain responses, and acquisition of an in vitro pro-inflammatory myofibroblast-like phenotype may contribute to the complex pathogenesis of the disorder. Finally, emerging findings from miRNA profiling of hEDS fibroblasts are discussed to add some novel biological aspects about hEDS etiopathogenesis.

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Section: Pathological Ecm Remodeling and Perturbation Of Cellular mentioning

confidence: 99%

Section: Pathological Ecm Remodeling and Perturbation Of Cellular mentioning

confidence: 99%

Section: Pathological Ecm Remodeling and Perturbation Of Cellular mentioning

confidence: 99%

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Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

Chiarelli

Ritelli

Zoppi

et al. 2019

Genes

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“…Last, “omic” technologies have uncovered ECM genes and proteins whose levels are predictive of cancer patient outcome [ 23 , 25 , 32 , 33 , 34 ]. However, while mutations in ECM genes have been linked to a plethora of diseases and syndromes [ 35 ], no study has focused on determining the presence and extent of genomic alterations and mutations in ECM genes in cancers, a crucial piece of information to further understanding of the tumor microenvironment (TME) [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome

Izzi

Davis

Naba

2020

Cancers

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The extracellular matrix (ECM) is a master regulator of all cellular functions and a major component of the tumor microenvironment. We previously defined the “matrisome” as the ensemble of genes encoding ECM proteins and proteins modulating ECM structure or function. While compositional and biomechanical changes in the ECM regulate cancer progression, no study has investigated the genomic alterations of matrisome genes in cancers and their consequences. Here, mining The Cancer Genome Atlas (TCGA) data, we found that copy number alterations and mutations are frequent in matrisome genes, even more so than in the rest of the genome. We also found that these alterations are predicted to significantly impact gene expression and protein function. Moreover, we identified matrisome genes whose mutational burden is an independent predictor of survival. We propose that studying genomic alterations of matrisome genes will further our understanding of the roles of this compartment in cancer progression and will lead to the development of innovative therapeutic strategies targeting the ECM.

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“…From these images, we appreciate how complex the structures are to connect cells to the underlying ECM and how complicated the ECM structure appears. The next article explores and documents how mutations in the genes for ECM components (Lamande and Bateman, 2020) cause a wide range of disorders throughout the body. The ECM includes secreted proteins that have very complicated biosynthetic pathways and, if disrupted, can cause stress in the cell organelles, especially the endoplasmic reticulum, so even non‐ECM proteins and factors can affect cellular function.…”

mentioning

confidence: 99%

Extracellular matrix: The proteins that function throughout the body

Svoboda¹,

Gordon

2020

The Anatomical Record

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The idea and meetings that planned this issue focused on extracellular matrix (ECM) started over 4 years ago. The invitations were sent to investigators over 2 years ago and manuscripts have been submitted, reviewed, and edited since the summer and fall of 2018. Most of the manuscripts were published in early view in 2019, and we are thrilled to share the final collection. This volume contains 6 reviews, 13 original research papers, and 4 remembrances. Marion (Emmy) Gordon and I organized the articles into seven topic areas, including ECM structure, genetics, and development; cancer; vascular structures and development; inflammation and wound healing; collagen in special structures; cornea and other ocular tissues; and extracellular vesicles. Anat Rec, 303:1509Rec, 303: -1513Rec, 303: , 2020 This special issue of The Anatomical Record explores the many roles of extracellular matrix (ECM), highlighting the work of investigators that study subjects ranging from development, to gene expression, to how the cornea maintains transparency, to how cells use extracellular vesicles (EVs) to communicate. Without the ECM, students would have less anatomy to study because tissue organization, cartilage, bones, or blood vessels would not exist. Fortunately, ECM is in nearly all animals, including the most primitive. ECM can be used to study evolution, development, wound healing, cancer, angiogenesis, vasculogenesis, fibrosis, and cell-cell communication. Our bones, muscles, blood vessels, and other organs are built from and supported by ECM molecules, enabling our bodies to perform specific functions that give us great freedom to walk, talk, and see our world. ECM molecules do not act alone but are found in supramolecular structures that may include growth factors and soluble and insoluble proteins. The fibrillar components include collagens, laminins, elastin, and fibronectin, while the nonfibrillar components include growth factors, glycosaminoglycans, and proteoglycans. Cells that populate the ECM are either the cells that produce the matrix molecules or transient cells that preside in ECM for short periods of time to facilitate bodily functions and repair injured tissue. This issue is divided into seven topic sections, including ECM structure, genetics and development, cancer, vascular structures and development, inflammation and wound healing, collagen in special structures, cornea and other ocular tissues, and EVs.An exploration of the ECM ultrastructure (cover, Keene and Tufa, 2020) comparing traditional fixation and embedding to high-pressure freeze-substitution (HPFS) is the first contribution to the special issue. The HPFS

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Genetic Disorders of the Extracellular Matrix

Cited by 61 publications

References 129 publications

Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome

Extracellular matrix: The proteins that function throughout the body

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