scholarly journals Matricellular Proteins in Cardiac Adaptation and Disease

2012 ◽  
Vol 92 (2) ◽  
pp. 635-688 ◽  
Author(s):  
Nikolaos G. Frangogiannis
Keyword(s):  
Therapeutic Potential ◽  
Current Knowledge ◽  
Tissue Growth ◽  
Primary Role ◽  
Matricellular Proteins ◽  
Ccn Family ◽  
Surface Receptors ◽  
Cardiac Adaptation ◽  
The Matrix ◽  
Cell Matrix Interactions

The term matricellular proteins describes a family of structurally unrelated extracellular macromolecules that, unlike structural matrix proteins, do not play a primary role in tissue architecture, but are induced following injury and modulate cell-cell and cell-matrix interactions. When released to the matrix, matricellular proteins associate with growth factors, cytokines, and other bioactive effectors and bind to cell surface receptors transducing signaling cascades. Matricellular proteins are upregulated in the injured and remodeling heart and play an important role in regulation of inflammatory, reparative, fibrotic and angiogenic pathways. Thrombospondin (TSP)-1, -2, and -4 as well as tenascin-C and -X secreted protein acidic and rich in cysteine (SPARC), osteopontin, periostin, and members of the CCN family (including CCN1 and CCN2/connective tissue growth factor) are involved in a variety of cardiac pathophysiological conditions, including myocardial infarction, cardiac hypertrophy and fibrosis, aging-associated myocardial remodeling, myocarditis, diabetic cardiomyopathy, and valvular disease. This review discusses the properties and characteristics of the matricellular proteins and presents our current knowledge on their role in cardiac adaptation and disease. Understanding the role of matricellular proteins in myocardial pathophysiology and identification of the functional domains responsible for their actions may lead to design of peptides with therapeutic potential for patients with heart disease.

scholarly journals CYR61 (CCN1) Is Essential for Placental Development and Vascular Integrity

2002 ◽  
Vol 22 (24) ◽  
pp. 8709-8720 ◽  
Author(s):  
Fan-E Mo ◽  
Andrew G. Muntean ◽  
Chih-Chiun Chen ◽  
Donna B. Stolz ◽  
Simon C. Watkins ◽  
...  
Keyword(s):  
Growth Factor ◽  
Vascular Diseases ◽  
Tissue Growth ◽  
Early Gene ◽  
Matricellular Proteins ◽  
Placental Development ◽  
Ccn Family ◽  
Aberrant Expression ◽  
Vascular Integrity ◽  
Vascular Insufficiency

ABSTRACT CYR61 (CCN1) is a member of the CCN family of secreted matricellular proteins that includes connective tissue growth factor (CCN2), NOV (CCN3), WISP-1 (CCN4), WISP-2 (CCN5), and WISP-3 (CCN6). First identified as the product of a growth factor-inducible immediate-early gene, CYR61 is an extracellular matrix-associated angiogenic inducer that functions as a ligand of integrin receptors to promote cell adhesion, migration, and proliferation. Aberrant expression of Cyr61 is associated with breast cancer, wound healing, and vascular diseases such as atherosclerosis and restenosis. To understand the functions of CYR61 during development, we have disrupted the Cyr61 gene in mice. We show here that Cyr61-null mice suffer embryonic death: ∼30% succumbed to a failure in chorioallantoic fusion, and the reminder perished due to placental vascular insufficiency and compromised vessel integrity. These findings establish CYR61 as a novel and essential regulator of vascular development. CYR61 deficiency results in a specific defect in vessel bifurcation (nonsprouting angiogenesis) at the chorioallantoic junction, leading to an undervascularization of the placenta without affecting differentiation of the labyrinthine syncytiotrophoblasts. This unique phenotype is correlated with impaired Vegf-C expression in the allantoic mesoderm, suggesting that CYR61-regulated expression of Vegf-C plays a role in vessel bifurcation. The genetic and molecular basis of vessel bifurcation is presently unknown, and these findings provide new insight into this aspect of angiogenesis.

scholarly journals The Roles of CCN1/CYR61 in Pulmonary Diseases

2020 ◽  
Vol 21 (21) ◽  
pp. 7810
Author(s):  
Yin Zhu ◽  
Sultan Almuntashiri ◽  
Yohan Han ◽  
Xiaoyun Wang ◽  
Payaningal Somanath ◽  
...  
Keyword(s):  
Tissue Growth ◽  
Pulmonary Diseases ◽  
Clinical Aspects ◽  
Chronic Obstructive ◽  
Matricellular Proteins ◽  
Ccn Family ◽  
Obstructive Pulmonary Disease ◽  
Regulation Of Proliferation ◽  
Therapeutic Development ◽  
Pulmonary Arterial

CCN1 (cysteine-rich 61, connective tissue growth factor, and nephroblastoma-1), previously named CYR61 (cysteine-rich angiogenic inducer 61) belongs to the CCN family of matricellular proteins. CCN1 plays critical roles in the regulation of proliferation, differentiation, apoptosis, angiogenesis, and fibrosis. Recent studies have extensively characterized the important physiological and pathological roles of CCN1 in various tissues and organs. In this review, we summarize both basic and clinical aspects of CCN1 in pulmonary diseases, including acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), lung fibrosis, pulmonary arterial hypertension (PAH), lung infection, and lung cancer. We also emphasize the important challenges for future investigations to better understand the CCN1 and its role in physiology and pathology, as well as the questions that need to be addressed for the therapeutic development of CCN1 antagonists in various lung diseases.

scholarly journals Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation

2016 ◽  
Vol 7 (2) ◽  
pp. 117-132 ◽  
Author(s):  
Katrina Viloria ◽  
Natasha J. Hill
Keyword(s):  
Alternative Splicing ◽  
Clinical Significance ◽  
Splice Variants ◽  
Single Gene ◽  
Matricellular Proteins ◽  
Surface Receptors ◽  
Cellular Processes ◽  
Clinical Disorders ◽  
The Matrix ◽  
Per Gene

AbstractMatricellular proteins influence wide-ranging fundamental cellular processes including cell adhesion, migration, growth and differentiation. They achieve this both through interactions with cell surface receptors and regulation of the matrix environment. Many matricellular proteins are also associated with diverse clinical disorders including cancer and diabetes. Alternative splicing is a precisely regulated process that can produce multiple isoforms with variable functions from a single gene. To date, the expression of alternate transcripts for the matricellular family has been reported for only a handful of genes. Here we analyse the evidence for alternative splicing across the matricellular family including the secreted protein acidic and rich in cysteine (SPARC), thrombospondin, tenascin and CCN families. We find that matricellular proteins have double the average number of splice variants per gene, and discuss the types of domain affected by splicing in matricellular proteins. We also review the clinical significance of alternative splicing for three specific matricellular proteins that have been relatively well characterised: osteopontin (OPN), tenascin-C (TNC) and periostin. Embracing the complexity of matricellular splice variants will be important for understanding the sometimes contradictory function of these powerful regulatory proteins, and for their effective clinical application as biomarkers and therapeutic targets.

scholarly journals Role of Matricellular CCN Proteins in Skeletal Muscle: Focus on CCN2/CTGF and Its Regulation by Vasoactive Peptides

2021 ◽  
Vol 22 (10) ◽  
pp. 5234
Author(s):  
Daniela L. Rebolledo ◽  
María José Acuña ◽  
Enrique Brandan
Keyword(s):  
Skeletal Muscle ◽  
Tissue Growth ◽  
Muscle Physiology ◽  
Ccn Proteins ◽  
Matricellular Proteins ◽  
Ccn Family ◽  
Kinin System ◽  
Muscle Fibrosis ◽  
Vasoactive Peptides ◽  
Skeletal Muscle Fibrosis

The Cellular Communication Network (CCN) family of matricellular proteins comprises six proteins that share conserved structural features and play numerous biological roles. These proteins can interact with several receptors or soluble proteins, regulating cell signaling pathways in various tissues under physiological and pathological conditions. In the skeletal muscle of mammals, most of the six CCN family members are expressed during embryonic development or in adulthood. Their roles during the adult stage are related to the regulation of muscle mass and regeneration, maintaining vascularization, and the modulation of skeletal muscle fibrosis. This work reviews the CCNs proteins’ role in skeletal muscle physiology and disease, focusing on skeletal muscle fibrosis and its regulation by Connective Tissue Growth factor (CCN2/CTGF). Furthermore, we review evidence on the modulation of fibrosis and CCN2/CTGF by the renin-angiotensin system and the kallikrein-kinin system of vasoactive peptides.

scholarly journals Regenerative properties of human extraembryonal organs in tissue engineering

2018 ◽  
Vol 20 (4) ◽  
pp. 192-198
Author(s):  
L I Kalyuzhnaya ◽  
O N Kharkevich ◽  
A A Schmidt ◽  
O V Protasov
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Umbilical Cord ◽  
Current Knowledge ◽  
Biological Properties ◽  
Engineering Structures ◽  
The Matrix ◽  
Cell Growth And Differentiation ◽  
And Function ◽  
Cell Matrix Interactions

The characteristics of the umbilical cord extracellular matrix are discussed relatively of their potential use for tissue engineering. The purpose of this review is to assess the current knowledge about using of homologous biomaterials with regenerative properties to create bioengineered structures. One of the most important components of tissue engineering - matrix (scaffold), resident cells can migrate, attach to it and function. Due to their structure, matrices should be easily integrated into the patient’s tissue and provide conditions for cell growth and differentiation. The cells that populate the matrix in the bioreactor before the transplantation of this construction, or resident cells recruited into the transplanted extracellular matrix), and cell- matrix interactions are absolutely necessary components of tissue engineering. Available commercial bioengineering products made from mammalian tissues have certain advantages and significant disadvantages due to the risks of immunological reactions and transmission of infectious agents. The transplantation of products from xenogenic materials is prohibited by law in the Russian Federation. The donor material is limited, receipt of human cadaver material requires a long period of legal registration, which has a detrimental effect on the biomaterial. Therefore, finding a suitable homologous biomaterial is ongoing. Due to the peculiarities of the embryonic phenotype, extraembryonic tissues have special biological properties, one of which is the scarless healing of wounds. Low immunogenicity, optimal mechanical properties of extracellular matrix, presence of cell adhesion molecules and growth factors promoting regeneration provide anti-inflammatory, anti-fibrotic, anti- scarring properties for tissue engineering structures from umbilical cord and amniotic membrane. Umbilical cord and amnion due to the availability and non-invasiveness of obtaining from healthy young donors are an excellent source of homologous biomaterial for extracting matrices, cells and hydrogels for tissue engineering and regenerative medicine.

scholarly journals Conjunction junction, what’s the function? CCN proteins as targets in fibrosis and cancers

2020 ◽  
Vol 318 (6) ◽  
pp. C1046-C1054 ◽  
Author(s):  
Andrew Leask
Keyword(s):  
Current Knowledge ◽  
Cellular Communication ◽  
Ccn Proteins ◽  
Clinical Consideration ◽  
Matricellular Proteins ◽  
Complex Molecules ◽  
Surface Receptors ◽  
Pathological Conditions ◽  
Cellular Communication Network

Cellular communication network (CCN) proteins are matricellular proteins that coordinate signaling among extracellular matrix, secreted proteins, and cell surface receptors. Their specific in vivo function is context-dependent, but they play profound roles in pathological conditions, such as fibrosis and cancers. Anti-CCN therapies are in clinical consideration. Only recently, however, has the function of these complex molecules begun to emerge. This review summarizes and interprets our current knowledge regarding these fascinating molecules and provides experimental evidence for their utility as therapeutic targets.

Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions

2014 ◽  
Vol 128 (3) ◽  
pp. 181-196 ◽  
Author(s):  
Satoshi Kubota ◽  
Masaharu Takigawa
Keyword(s):  
Tissue Growth ◽  
The Novel ◽  
Matricellular Proteins ◽  
Ccn Family ◽  
Signalling Molecules ◽  
Pathological Conditions ◽  
Molecular Action ◽  
Family Protein ◽  
Biological Outcomes ◽  
Extracellular Signalling

CCN family protein 2 (CCN2), also widely known as connective tissue growth factor (CTGF), is one of the founding members of the CCN family of matricellular proteins. Extensive investigation on CCN2 over decades has revealed the novel molecular action and functional properties of this unique signalling modulator. By its interaction with multiple molecular counterparts, CCN2 yields highly diverse and context-dependent biological outcomes in a variety of microenvironments. Nowadays, CCN2 is recognized to conduct the harmonized development of relevant tissues, such as cartilage and bone, in the skeletal system, by manipulating extracellular signalling molecules involved therein by acting as a hub through a web. However, on the other hand, CCN2 occasionally plays profound roles in major human biological disorders, including fibrosis and malignancies in major organs and tissues, by modulating the actions of key molecules involved in these clinical entities. In this review, the physiological and pathological roles of this unique protein are comprehensively summarized from a molecular network-based viewpoint of CCN2 functionalities.

Identification and characterization of collagen-like glycosylation and hydroxylation of CCN1

Glycobiology ◽  
2019 ◽  
Vol 29 (10) ◽  
pp. 696-704
Author(s):  
Yudai Ishizawa ◽  
Yuki Niwa ◽  
Takehiro Suzuki ◽  
Ryota Kawahara ◽  
Naoshi Dohmae ◽  
...  
Keyword(s):  
The Novel ◽  
Matricellular Proteins ◽  
Ccn Family ◽  
Multifunctional Protein ◽  
Surface Receptors ◽  
Extracellular Region ◽  
Defective Mutant ◽  
Overexpressing Cell

Abstract CCN1 is a secreted protein and belongs to the CCN family of matricellular proteins. CCN1 binds to various cell surface receptors; thus, CCN1 has important functions in cell proliferation, migration and angiogenesis through a variety of signaling pathways. We have reported that CCN1 is O-fucosylated and that this O-fucosylation regulates the secretion of CCN1 into the extracellular region. In this study, we detected collagen-like glycosylation and hydroxylation at Lys203 of recombinant CCN1 by mass spectrometry. We then examined the role of collagen-like glycosylation in the functions of CCN1. As a result, we found that a deficiency in collagen-like glycosylation decreased the secretion of CCN1 using wild-type CCN1- and collagen-like glycosylation-defective mutant CCN1-overexpressing cell lines. Further, knockout of lysyl hydroxylase3, a multifunctional protein with hydroxylase and glucosyltransferase activities, impaired the secretion and glycosylation level of recombinant CCN1. Previous studies reported that collagen glycosylation of Lys residues mediated by lysyl hydroxylase3 is glucosyl-galactosyl-hydroxylation, presuming that this collagen-like glycosylation detected at Lys203 of recombinant CCN1 in this study might be glucosyl-galactosyl-hydroxylation. Taken together, our results demonstrate the novel function of the collagen-like glycosylation of CCN1 and suggest that lysyl hydroxylase3-mediated glycosylation is important for CCN1 secretion.

scholarly journals CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology

2021 ◽  
Author(s):  
Veronica Giusti ◽  
Katia Scotlandi
Keyword(s):  
Musculoskeletal System ◽  
Adult Life ◽  
Current Understanding ◽  
Minor Role ◽  
Ccn Proteins ◽  
Matricellular Proteins ◽  
Ccn Family ◽  
Surface Receptors ◽  
Cell Commitment ◽  
A Minor

AbstractThe acronym for the CCN family was recently revised to represent “cellular communication network”. These six, small, cysteine-enriched and evolutionarily conserved proteins are secreted matricellular proteins, that convey and modulate intercellular communication by interacting with structural proteins, signalling factors and cell surface receptors. Their role in the development and physiology of musculoskeletal system, constituted by connective tissues where cells are interspersed in the cellular matrix, has been broadly studied. Previous research has highlighted a crucial balance of CCN proteins in mesenchymal stem cell commitment and a pivotal role for CCN1, CCN2 and their alter ego CCN3 in chondrogenesis and osteogenesis; CCN4 plays a minor role and the role of CCN5 and CCN6 is still unclear. CCN proteins also participate in osteoclastogenesis and myogenesis. In adult life, CCN proteins serve as mechanosensory proteins in the musculoskeletal system providing a steady response to environmental stimuli and participating in fracture healing. Substantial evidence also supports the involvement of CCN proteins in inflammatory pathologies, such as osteoarthritis and rheumatoid arthritis, as well as in cancers affecting the musculoskeletal system and bone metastasis. These matricellular proteins indeed show involvement in inflammation and cancer, thus representing intriguing therapeutic targets. This review discusses the current understanding of CCN proteins in the musculoskeletal system as well as the controversies and challenges associated with their multiple and complex roles, and it aims to link the dispersed knowledge in an effort to stimulate and guide readers to an area that the writers consider to have significant impact and relevant potentialities.

scholarly journals CYR61 (CCN1) overexpression induces lung injury in mice

2015 ◽  
Vol 308 (8) ◽  
pp. L759-L765 ◽  
Author(s):  
Serge Grazioli ◽  
Sucheol Gil ◽  
Dowon An ◽  
Osamu Kajikawa ◽  
Alex W. Farnand ◽  
...  
Keyword(s):  
Lung Injury ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Tissue Growth ◽  
Alveolar Epithelial Cells ◽  
Heparin Binding ◽  
Matricellular Proteins ◽  
Ccn Family ◽  
Alveolar Epithelial ◽  
Immunohistochemical Studies

Cysteine-rich protein-61 (CYR61), also known as connective tissue growth factor, CYR61, and nephroblastoma overexpressed gene 1 (CCN1), is a heparin-binding protein member of the CCN family of matricellular proteins. Gene expression profiles showed that Cyr61 is upregulated in human acute lung injury (ALI), but its functional role is unclear. We hypothesized that CYR61 contributes to ALI in mice. First, we demonstrated that CYR61 expression increases after bleomycin-induced lung injury. We then used adenovirus-mediated gene transfer to determine whether CYR61 overexpression in the lungs was sufficient to cause ALI. Mice instilled with CYR61 adenovirus showed greater weight loss, increased bronchoalveolar lavage total neutrophil counts, increased protein concentrations, and increased mortality compared with mice instilled with empty-vector adenovirus. Immunohistochemical studies in lungs from humans with idiopathic pulmonary fibrosis revealed CYR61 expression on the luminal membrane of alveolar epithelial cells in areas of injury. We conclude that CYR61 is upregulated in ALI and that CYR61 overexpression exacerbates ALI in mice.

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