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 WISP-1 is a Wnt-1- and β-catenin-responsive oncogene

2000 ◽  
Vol 14 (5) ◽  
pp. 585-595 ◽  
Author(s):  
Lifeng Xu ◽  
Ryan B. Corcoran ◽  
James W. Welsh ◽  
Diane Pennica ◽  
Arnold J. Levine
Keyword(s):  
Transcriptional Activation ◽  
Rat Kidney ◽  
Soft Agar ◽  
Minor Role ◽  
Morphological Transformation ◽  
Ccn Family ◽  
Cellular Attachment ◽  
Normal Rat ◽  
Kidney Fibroblast ◽  
A Minor

WISP-1 (Wnt-1 induced secreted protein 1) is a member of the CCN family of growth factors. This study identifies WISP-1 as a β-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and β-catenin expression. TCF/LEF sites played a minor role, whereas the CREB site played an important role in this transcriptional activation. WISP-1 demonstrated oncogenic activities; overexpression of WISP-1 in normal rat kidney fibroblast cells (NRK-49F) induced morphological transformation, accelerated cell growth, and enhanced saturation density. Although these cells did not acquire anchorage-independent growth in soft agar, they readily formed tumors in nude mice, suggesting that appropriate cellular attachment is important for signaling oncogenic events downstream of WISP-1.

scholarly journals Targeting CCN Proteins in Rheumatoid Arthritis and Osteoarthritis

2021 ◽  
Vol 22 (9) ◽  
pp. 4340
Author(s):  
Iona J. MacDonald ◽  
Chien-Chung Huang ◽  
Shan-Chi Liu ◽  
Yen-You Lin ◽  
Chih-Hsin Tang
Keyword(s):  
Rheumatoid Arthritis ◽  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Wound Healing ◽  
Evidence Base ◽  
Ccn Proteins ◽  
Matricellular Proteins ◽  
Substantial Evidence ◽  
Ccn Family ◽  
Cellular Processes

The CCN family of matricellular proteins (CYR61/CCN1, CTGF/CCN2, NOV/CCN3 and WISP1-2-3/CCN4-5-6) are essential players in the key pathophysiological processes of angiogenesis, wound healing and inflammation. These proteins are well recognized for their important roles in many cellular processes, including cell proliferation, adhesion, migration and differentiation, as well as the regulation of extracellular matrix differentiation. Substantial evidence implicates four of the proteins (CCN1, CCN2, CCN3 and CCN4) in the inflammatory pathologies of rheumatoid arthritis (RA) and osteoarthritis (OA). A smaller evidence base supports the involvement of CCN5 and CCN6 in the development of these diseases. This review focuses on evidence providing insights into the involvement of the CCN family in RA and OA, as well as the potential of the CCN proteins as therapeutic targets in these diseases.

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 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.

scholarly journals The Aspects of CCN Protein Family on Breast Cancer

2021 ◽  
Author(s):  
Abu Saim Mohammad Saikat ◽  
Kazi Ahsan Ahmed ◽  
Md. Saddam ◽  
Afsana Mimi ◽  
Tasnin Al Hasib ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Protein Family ◽  
Ccn Proteins ◽  
Biological Interactions ◽  
Immune Functions ◽  
Matricellular Proteins ◽  
Ccn Family ◽  
Aberrant Expression ◽  
And Migration

CCNs are specific type of matricellular proteins, which are essential signaling molecules, and play multiple roles in multicellular eukaryotes. This family of proteins consists of six separate members in mammals. The architecture of CCN proteins is multimodular and comprises four distinct motifs. CCN proteins achieve their specific physiological functions by binding to integrin receptors. The CCN family has been implicated in both cure and disease with impacts on biological interactions, such as cell adhesion, chemotaxis and migration, mitogenesis, cell survival, angiogenesis, differentiation, tumorigenesis, immune functions, chondrogenesis, and wound healing. Breast cancer is the most commonly diagnosed cancer worldwide and the leading cause of cancer mortality among women triggered by atypical expression of CCNs. A favorable or unfavorable association between various CCNs has been reported in patients with breast carcinomas. Aberrant expression of CCN1 intensifies the proliferation of epithelial cells that line the lobes and ducts of the breast. Evidence also shows that the expression of CCN2 can ameliorate tumor growth and metastasis. However, CCN3 (NOV), CCN5 (WISP-2), and CCN6 (WISP-3) are consistent with neoplastic development and metastasis repression. Particular CCN members can develop tumors and cancer progression, whereas others can competitively counter the processes. Several studies have been conducted on CCN proteins and cancer in recent years. In our study, we intend to provide an overview of those research works while keeping breast carcinoma on focus. We believe that the importance of the CCN protein family in breast cancer should be reconsidered.

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 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.

The Effect of Path Length and Display Size on Memory for Spatial Information

2012 ◽  
Vol 59 (3) ◽  
pp. 147-152 ◽  
Author(s):  
Katherine Guérard ◽  
Sébastien Tremblay
Keyword(s):  
Path Length ◽  
Potential Role ◽  
Spatial Information ◽  
Recall Performance ◽  
Minor Role ◽  
Length Effect ◽  
Serial Memory ◽  
Fixed Reference ◽  
A Minor

In serial memory for spatial information, some studies showed that recall performance suffers when the distance between successive locations increases relatively to the size of the display in which they are presented (the path length effect; e.g., Parmentier et al., 2005) but not when distance is increased by enlarging the size of the display (e.g., Smyth & Scholey, 1994). In the present study, we examined the effect of varying the absolute and relative distance between to-be-remembered items on memory for spatial information. We manipulated path length using small (15″) and large (64″) screens within the same design. In two experiments, we showed that distance was disruptive mainly when it is varied relatively to a fixed reference frame, though increasing the size of the display also had a small deleterious effect on recall. The insertion of a retention interval did not influence these effects, suggesting that rehearsal plays a minor role in mediating the effects of distance on serial spatial memory. We discuss the potential role of perceptual organization in light of the pattern of results.

Use of Different Tissue Thromboplastins in the Control of Anticoagulant-Therapy

1958 ◽  
Vol 02 (05/06) ◽  
pp. 462-480 ◽  
Author(s):  
Marc Verstraete ◽  
Patricia A. Clark ◽  
Irving S. Wright
Keyword(s):  
Prothrombin Time ◽  
Anticoagulant Therapy ◽  
Factor Vii ◽  
Rabbit Brain ◽  
Minor Role ◽  
Rabbit Lung ◽  
Coagulation Mechanism ◽  
Time Test ◽  
The One ◽  
A Minor

SummaryAn analysis of the results of prothrombin time tests with different types of thromboplastins sheds some light on the problem why the administration of coumarin is difficult to standardize in different centers. Our present ideas on the subject, based on experimental data may be summarized as follows.Several factors of the clotting mechanism are influenced by coumarin derivatives. The action of some of these factors is by-passed in the 1-stage prothrombin time test. The decrease of the prothrombin and factor VII levels may be evaluated in the 1-stage prothrombin time determination (Quick-test). The prolongation of the prothrombin times are, however, predominantly due to the decrease of factor VII activity, the prothrombin content remaining around 50 per cent of normal during an adequate anticoagulant therapy. It is unlikely that this degree of depression of prothrombin is of major significance in interfering with the coagulation mechanism in the protection against thromboembolism. It may, however, play a minor role, which has yet to be evaluated quantitatively. An exact evaluation of factor VII is, therefore, important for the guidance of anticoagulant therapy and the method of choice is the one which is most sensitive to changes in factor VII concentration. The 1-stage prothrombin time test with a rabbit lung thromboplastin seems the most suitable method because rabbit brain preparations exhibit a factor VII-like activity that is not present in rabbit lung preparations.

Produktivkraft als Versprechen

2016 ◽  
Vol 46 (185) ◽  
pp. 621-638 ◽  
Author(s):  
Christian Siefkes
Keyword(s):  
Private Consumption ◽  
Minor Role ◽  
Progressive Reduction ◽  
Internal Forces ◽  
A Minor

The ‘Fragment on Machines’ from Marx’s Grundrisse is often cited as an argument that the internal forces of capitalism will lead to its doom. But the argument that the progressive reduction of labor must doom capitalism lacks a proper foundation, as a comparison with the ‘Schemes of Reproduction’ given in Capital II shows. The latter, however, aren’t fully convincing either. In reality, more depends on the private consumption of capitalists than either model recognizes. Ultimately, most can be made of the ‘Fragment on Machines’ by reading it not as an exposure of capitalism’s internal contractions, but as a discussion of a possible communist future where labor (or work) will play but a minor role.

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