scholarly journals Distinct extracellular-matrix remodeling events precede symptoms of inflammation

2019 ◽  
Author(s):  
Elee Shimshoni ◽  
Idan Adir ◽  
Ran Afik ◽  
Inna Solomonov ◽  
Anjana Shenoy ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Clinical Symptoms ◽  
Human Subjects ◽  
Disease Onset ◽  
Matrix Remodeling ◽  
Cellular Processes ◽  
Wide Range ◽  
The Matrix ◽  
Bowel Diseases ◽  
Clinical Potential

AbstractIdentification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular matrix. In this study, we used colitis models for investigating extracellular-matrix dynamics during disease onset, while treating the matrix as a complete and defined entity. Through the analysis of matrix structure, stiffness and composition, we unexpectedly revealed that even prior to the first clinical symptoms, the colon displays its own unique extracellular-matrix signature and found specific markers of clinical potential, which were also validated in human subjects. We also show that the emergence of this pre-symptomatic matrix is mediated by sub-clinical infiltration of neutrophils and monocytes bearing remodeling enzymes. Remarkably, whether the inflammation is chronic or acute, its matrix signature converges at pre-symptomatic states. We suggest that the existence of a pre-symptomatic extracellular-matrix is general and relevant to a wide range of diseases.

scholarly journals Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

2021 ◽  
Vol 8 ◽  
Author(s):  
Liena E. O. Elsayed ◽  
Isra Zuhair Eltazi ◽  
Ammar E. Ahmed ◽  
Giovanni Stevanin
Keyword(s):  
Clinical Symptoms ◽  
Disease Onset ◽  
Lower Limbs ◽  
Special Focus ◽  
Clinical Genetic ◽  
Comprehensive Overview ◽  
Functional Studies ◽  
Hereditary Spastic Paraplegias ◽  
Wide Range ◽  
Complex Forms

Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

scholarly journals Induction of Extracellular Matrix-Remodeling Genes by the Senescence-Associated Protein APA-1

2002 ◽  
Vol 22 (21) ◽  
pp. 7385-7397 ◽  
Author(s):  
Jennifer A. Benanti ◽  
Dawnnica K. Williams ◽  
Kristin L. Robinson ◽  
Harvey L. Ozer ◽  
Denise A. Galloway
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Zinc Finger Protein ◽  
Kinase Inhibitor ◽  
Human Fibroblasts ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Telomere Attrition ◽  
Cyclin Dependent Kinase Inhibitor ◽  
The Matrix

ABSTRACT Human fibroblasts undergo cellular senescence after a finite number of divisions, in response to the erosion of telomeres. In addition to being terminally arrested in the cell cycle, senescent fibroblasts express genes that are normally induced upon wounding, including genes that remodel the extracellular matrix. We have identified the novel zinc finger protein APA-1, whose expression increased in senescent human fibroblasts independent of telomere shortening. Extended passage, telomerase-immortalized fibroblasts had increased levels of APA-1 as well as the cyclin-dependent kinase inhibitor p16. In fibroblasts, APA-1 was modified by the ubiquitin-like protein SUMO-1, which increased APA-1 half-life, possibly by blocking ubiquitin-mediated degradation. Overexpression of APA-1 did not cause cell cycle arrest; but, it induced transcription of the extracellular matrix-remodeling genes MMP1 and PAI2, which are associated with fibroblast senescence. MMP1 and PAI2 transcript levels also increased in telomerase-immortalized fibroblasts that had high levels of APA-1, demonstrating that the matrix-remodeling phenotype of senescent fibroblasts was not induced by telomere attrition alone. APA-1 was able to transactivate and bind to the MMP1 promoter, suggesting that APA-1 is a transcription factor that regulates expression of matrix-remodeling genes during fibroblast senescence.

scholarly journals The matrix in focus: new directions in extracellular matrix research from the 2021 ASMB hybrid meeting

Biology Open ◽  
2022 ◽  
Vol 11 (1) ◽  
Author(s):  
Bryan A. Nerger ◽  
Tia M. Jones ◽  
Keron W. J. Rose ◽  
Anna Barqué ◽  
Justin S. Weinbaum ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Scientific Meeting ◽  
Model Systems ◽  
Scientific Conference ◽  
Architectural Support ◽  
Therapeutic Modalities ◽  
Cellular Processes ◽  
The Matrix ◽  
American Society ◽  
Molecular Signals

ABSTRACT The extracellular matrix (ECM) is a complex assembly of macromolecules that provides both architectural support and molecular signals to cells and modulate their behaviors. Originally considered a passive mechanical structure, decades of research have since demonstrated how the ECM dynamically regulates a diverse set of cellular processes in development, homeostasis, and disease progression. In September 2021, the American Society for Matrix Biology (ASMB) organized a hybrid scientific meeting, integrating in-person and virtual formats, to discuss the latest developments in ECM research. Here, we highlight exciting scientific advances that emerged from the meeting including (1) the use of model systems for fundamental and translation ECM research, (2) ECM-targeting approaches as therapeutic modalities, (3) cell-ECM interactions, and (4) the ECM as a critical component of tissue engineering strategies. In addition, we discuss how the ASMB incorporated mentoring, career development, and diversity, equity, and inclusion initiatives in both virtual and in-person events. Finally, we reflect on the hybrid scientific conference format and how it will help the ASMB accomplish its mission moving forward.

Biologic Therapy in Crohn’s Disease–What We Have Learnt So Far

2020 ◽  
Vol 21 (8) ◽  
pp. 792-806
Author(s):  
Kinga Majchrzak ◽  
Jakub Fichna
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Biologic Therapy ◽  
Clinical Symptoms ◽  
Autoimmune Disorder ◽  
Biological Drugs ◽  
Wide Range ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Maintenance Of Remission

Crohn’s disease (CD) is an autoimmune disorder from the group of inflammatory bowel diseases. The etiology of CD is not clear; currently, the interaction between the genetic, immunological and environmental factors is assumed as the cause of the disease. Partial knowledge of those factors has led to the development of drugs, which control the clinical symptoms and improve the overall condition of the infected; the main objective of the modern therapeutic strategies is the induction and maintenance of remission. Among the wide range of available treatments, older generation molecules: mesalazine, corticosteroids and thiopurine derivatives as well as biological drugs and biosimilars can be distinguished. Moreover, some novel biologics and small molecule drugs have shown potential in CD clinical trials, providing safe and effective results. This article provides an overview of the achievements in the field of biologic therapy, its efficacy and safety with an indication of future directions in CD treatment.

scholarly journals Localization and temporal regulation of tissue inhibitors of metalloproteinases 3 and 4 in bovine preovulatory follicles

Reproduction ◽  
2004 ◽  
Vol 128 (5) ◽  
pp. 555-564 ◽  
Author(s):  
Qinglei Li ◽  
Leanne J Bakke ◽  
J Richard Pursley ◽  
George W Smith
Keyword(s):  
Extracellular Matrix ◽  
Immunohistochemical Localization ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Matrix Remodeling ◽  
Tissue Inhibitors ◽  
Temporal Regulation ◽  
Thecal Cells ◽  
Preovulatory Follicles ◽  
The Matrix ◽  
Gonadotropin Surge

The matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are potential regulators of the focalized extracellular matrix degradation required for ovulation. The objectives of the present study were to determine localization and temporal regulation of TIMP-3 and TIMP-4 mRNA and protein in bovine preovulatory follicles. Ovaries containing preovulatory follicles were collected at 0, 12 and 20 h after GnRH injection for real-time PCR quantification of TIMP-3 and TIMP-4 mRNAs and immunohistochemical localization studies. Additional samples collected at 0, 6, 12, 18 and 24 h post GnRH injection were subjected to Western analysis to determine temporal changes in TIMP-3 and TIMP-4 proteins in the apex and base of preovulatory follicles. Results indicate the gonadotropin surge regulates TIMP-3 and TIMP-4 expression. TIMP-3 and TIMP-4 mRNAs increased within 12 h after GnRH injection. TIMP-3 protein was localized to granulosal and thecal layers of preovulatory follicles and adjacent ovarian stroma, whereas TIMP-4 immunoreactivity was localized to granulosal and thecal cells and ovarian blood vessels. Amounts of TIMP-3 and TIMP-4 proteins in the follicular apex peaked within 12 h post GnRH injection and subsequently declined by 24 h. However, amounts of TIMP-3 and TIMP-4 proteins in the base were not elevated after GnRH administration. Results demonstrate that mRNA and protein for both TIMP-3 and TIMP-4 are increased in bovine preovulatory follicles following the gonadotropin surge. Coordinate expression of TIMPs and MMPs may help regulate the extracellular matrix remodeling characteristic of the ovulatory process.

scholarly journals The Role of Extracellular Matrix Components in Inflammatory Bowel Diseases

2021 ◽  
Vol 10 (5) ◽  
pp. 1122
Author(s):  
Alicja Derkacz ◽  
Paweł Olczyk ◽  
Krystyna Olczyk ◽  
Katarzyna Komosinska-Vassev
Keyword(s):  
Extracellular Matrix ◽  
Inflammatory Bowel Diseases ◽  
Healing Process ◽  
Immunological Response ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Intestinal Fibrosis ◽  
Extracellular Matrix Components ◽  
Bowel Diseases ◽  
Inflammatory Bowel

The remodeling of extracellular matrix (ECM) within the intestine tissues, which simultaneously involves an increased degradation of ECM components and excessive intestinal fibrosis, is a defining trait of the progression of inflammatory bowel diseases (IBDs), which include ulcerative colitis (UC) and Crohn’s disease (CD). The increased activity of proteases, especially matrix metalloproteinases (MMPs), leads to excessive degradation of the extracellular matrix and the release of protein and glycoprotein fragments, previously joined with the extracellular matrix, into the circulation. MMPs participate in regulating the functions of the epithelial barrier, the immunological response, and the process of wound healing or intestinal fibrosis. At a later stage of fibrosis during IBD, excessive formation and deposition of the matrix is observed. To assess changes in the extracellular matrix, quantitative measurement of the concentration in the blood of markers dependent on the activity of proteases, involved in the breakdown of extracellular matrix proteins as well as markers indicating the formation of a new ECM, has recently been proposed. This paper describes attempts to use the quantification of ECM components as markers to predict intestinal fibrosis and evaluate the healing process of the gut. The markers which reflect increased ECM degradation, together with the ones which show the process of creating a new matrix during IBD, allow the attainment of important information regarding the changes in the intestinal tissue, epithelial integrity and extracellular matrix remodeling. This paper contains evidence confirming that ECM remodeling is an integral part of directional cell signaling in the progression of IBD, and not only a basis for the ongoing processes.

Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism

2015 ◽  
Vol 309 (8) ◽  
pp. E691-E714 ◽  
Author(s):  
Amaia Rodríguez ◽  
Silvia Ezquerro ◽  
Leire Méndez-Giménez ◽  
Sara Becerril ◽  
Gema Frühbeck
Keyword(s):  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Glucose Disposal ◽  
Cytokine Signaling ◽  
Matrix Remodeling ◽  
Nonalcoholic Fatty Liver ◽  
Brown Adipose ◽  
Wide Range ◽  
Beige Fat

Adipose tissue constitutes an extremely active endocrine organ with a network of signaling pathways enabling the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a huge variety of hormones, cytokines, complement and growth factors, extracellular matrix proteins, and vasoactive factors, collectively termed adipokines. Obesity is associated with adipose tissue dysfunction leading to the onset of several pathologies including type 2 diabetes, dyslipidemia, nonalcoholic fatty liver, or hypertension, among others. The mechanisms underlying the development of obesity and its associated comorbidities include the hypertrophy and/or hyperplasia of adipocytes, adipose tissue inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipokines. Recently, the potential role of brown and beige adipose tissue in the protection against obesity has been also recognized. In contrast to white adipocytes, which store energy in the form of fat, brown and beige fat cells display energy-dissipating capacity through the promotion of triacylglycerol clearance, glucose disposal, and generation of heat for thermogenesis. Identification of the morphological and molecular changes in white, beige, and brown adipose tissue during weight gain is of utmost relevance for the identification of pharmacological targets for the treatment of obesity and its associated metabolic diseases.

scholarly journals The Plasminogen–Activator Plasmin System in Physiological and Pathophysiological Angiogenesis

2021 ◽  
Vol 23 (1) ◽  
pp. 337
Author(s):  
Asmaa Anwar Ismail ◽  
Baraah Tariq Shaker ◽  
Khalid Bajou
Keyword(s):  
Extracellular Matrix ◽  
Plasminogen Activator ◽  
Serine Proteases ◽  
Plasminogen Activator Inhibitor ◽  
Cellular Migration ◽  
Tissue Type ◽  
Matrix Remodeling ◽  
Plasminogen Activator Inhibitor 1 ◽  
Wide Range ◽  
Pai 1

Angiogenesis is a process associated with the migration and proliferation of endothelial cells (EC) to form new blood vessels. It is involved in various physiological and pathophysiological conditions and is controlled by a wide range of proangiogenic and antiangiogenic molecules. The plasminogen activator–plasmin system plays a major role in the extracellular matrix remodeling process necessary for angiogenesis. Urokinase/tissue-type plasminogen activators (uPA/tPA) convert plasminogen into the active enzyme plasmin, which in turn activates matrix metalloproteinases and degrades the extracellular matrix releasing growth factors and proangiogenic molecules such as the vascular endothelial growth factor (VEGF-A). The plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of uPA and tPA, thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively. Paradoxically, PAI-1, which is expressed by EC during angiogenesis, is elevated in several cancers and is found to promote angiogenesis by regulating plasmin-mediated proteolysis and by promoting cellular migration through vitronectin. The urokinase-type plasminogen activator receptor (uPAR) also induces EC cellular migration during angiogenesis via interacting with signaling partners. Understanding the molecular functions of the plasminogen activator plasmin system and targeting angiogenesis via blocking serine proteases or their interactions with other molecules is one of the major therapeutic strategies scientists have been attracted to in controlling tumor growth and other pathological conditions characterized by neovascularization.

The matrix reorganized: extracellular matrix remodeling and integrin signaling

2006 ◽  
Vol 18 (5) ◽  
pp. 463-471 ◽  
Author(s):  
Melinda Larsen ◽  
Vira V Artym ◽  
J Angelo Green ◽  
Kenneth M Yamada
Keyword(s):  
Extracellular Matrix ◽  
Integrin Signaling ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
The Matrix
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