scholarly journals Profile of Matrix-Remodeling Proteinases in Osteoarthritis: Impact of Fibronectin

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 40 ◽  
Author(s):  
Selene Pérez-García ◽  
Mar Carrión ◽  
Irene Gutiérrez-Cañas ◽  
Raúl Villanueva-Romero ◽  
David Castro ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Three Dimensional ◽  
Matrix Remodeling ◽  
Synovial Joint ◽  
Surface Receptors ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Fibronectin Fragments ◽  
Macromolecular Network ◽  
A Disintegrin And Metalloproteinase

The extracellular matrix (ECM) is a complex and specialized three-dimensional macromolecular network, present in nearly all tissues, that also interacts with cell surface receptors on joint resident cells. Changes in the composition and physical properties of the ECM lead to the development of many diseases, including osteoarthritis (OA). OA is a chronic degenerative rheumatic disease characterized by a progressive loss of synovial joint function as a consequence of the degradation of articular cartilage, also associated with alterations in the synovial membrane and subchondral bone. During OA, ECM-degrading enzymes, including urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), cleave ECM components, such as fibronectin (Fn), generating fibronectin fragments (Fn-fs) with catabolic properties. In turn, Fn-fs promote activation of these proteinases, establishing a degradative and inflammatory feedback loop. Thus, the aim of this review is to update the contribution of ECM-degrading proteinases to the physiopathology of OA as well as their modulation by Fn-fs.

Relation of Urokinase-Type Plasminogen Activator Expression to Presence and Severity of Atherosclerotic Lesions in Human Coronary Arteries

1998 ◽  
Vol 79 (03) ◽  
pp. 579-586 ◽  
Author(s):  
Teresa Padró ◽  
Martin Steins ◽  
Chang-Xun Li ◽  
Kurt Schmid ◽  
Dieter Hammel ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Coronary Arteries ◽  
Plasminogen Activator Inhibitor ◽  
Matrix Remodeling ◽  
Plasminogen Activator Inhibitor 1 ◽  
Atherosclerotic Lesions ◽  
Plaque Disruption ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Tissue Specimens

SummaryUrokinase-type plasminogen activator (UPA) has been implicated in a broad spectrum of pathological processes – e.g. cell adhesion, migration and proliferation and matrix remodeling – that are considered important features of atherogenesis and plaque disruption. In this study, we have analyzed the content and expression of UPA in human coronary arteries and its relation to the presence and severity of atherosclerotic lesions. Segments of coronary arteries obtained from human heart explants (n = 15) were classified by the presence and types of atherosclerotic lesions. UPA was quantitatively determined in protein extracts of the intimal and medial layers. In situ hybridization and immunohistochemical analyses were performed on serial sections of representative tissue specimens. UPA was detected in the extracts as pro-UPA, UPA complexed to plasminogen activator inhibitor-1, or as otherwise inactive UPA antigen, but not in the active two-chain form. Both functional and total UPA were increased several-fold in extracts of advanced lesions, while the ratios of functional over total UPA showed the opposite trend suggesting enhanced UPA inactivation and turnover. UPA expression in early atherosclerotic lesions was particularly prominent in areas of proliferating SMCs in the abluminal part of the neointima, whereas in advanced lesions UPA was widely expressed in macrophage-rich areas adjacent to the rims and shoulder regions of the necrotic cores. The results strongly suggest a causal involvement of UPA in coronary atherogenesis and its clinical outcome.

scholarly journals Systematic Analysis of Protease Gene Expression in the Rhesus Macaque Ovulatory Follicle: Metalloproteinase Involvement in Follicle Rupture

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3963-3974 ◽  
Author(s):  
Marina C. Peluffo ◽  
Melinda J. Murphy ◽  
Serena Talcott Baughman ◽  
Richard L. Stouffer ◽  
Jon D. Hennebold
Keyword(s):  
Rhesus Macaques ◽  
Cathepsin L ◽  
Protease Gene ◽  
Mrna Levels ◽  
Systematic Analysis ◽  
Ovulatory Follicle ◽  
Follicle Rupture ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
A Disintegrin And Metalloproteinase

Protease genes were identified that exhibited increased mRNA levels before and immediately after rupture of the naturally selected, dominant follicle of rhesus macaques at specific intervals after an ovulatory stimulus. Quantitative real-time PCR validation revealed increased mRNA levels for matrix metalloproteinase (MMP1, MMP9, MMP10, and MMP19) and a disintegrin and metalloproteinase with thrombospondin-like repeats (ADAMTS1, ADAMTS4, ADAMTS9, and ADAMTS15) family members, the cysteine protease cathepsin L (CTSL), the serine protease urokinase-type plasminogen activator (PLAU), and the aspartic acid protease pepsinogen 5 (PGA5). With the exception of MMP9, ADAMTS1, and PGA5, mRNA levels for all other up-regulated proteases increased significantly (P < 0.05) 12 h after an ovulatory human chorionic gonadotropin (hCG) bolus. MMP1, -10, and -19; ADAMTS1, -4, and -9; CTSL; PLAU; and PGA5 also exhibited a secondary increase in mRNA levels in 36-h postovulatory follicles. To further determine metalloproteinase involvement in ovulation, vehicle (n = 4) or metalloproteinase inhibitor (GM6001, 0.5 μg/follicle, n = 8) was injected into the preovulatory follicle at the time of hCG administration. Of the eight GM6001-injected follicles, none displayed typical stigmata indicative of ovulation at 72 h after hCG; whereas all four vehicle-injected follicles ovulated. No significant differences in mean luteal progesterone levels or luteal phase length occurred between the two groups. Subsequent histological analysis revealed that vehicle-injected follicles ruptured, whereas GM6001-injected follicles did not, as evidenced by an intact stroma and trapped oocytes (n = 3). These findings demonstrate metalloproteinases are critical for follicle rupture in primates, and blocking their activity would serve as a novel, nonhormonal means to achieve contraception.

Endogenously produced urokinase-type plasminogen activator is a major determinant of the basal level of activated ERK/MAP kinase and prevents apoptosis in MDA-MB-231 breast cancer cells

2001 ◽  
Vol 114 (18) ◽  
pp. 3387-3396
Author(s):  
Zhong Ma ◽  
Donna J. Webb ◽  
Minji Jo ◽  
Steven L. Gonias
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Plasminogen Activator ◽  
Specific Antibody ◽  
Breast Cancer Cells ◽  
Feedback Loop ◽  
Erk Signaling ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator

Urokinase-type plasminogen activator (uPA) binds to the uPA receptor (uPAR) and activates the Ras-extracellular signal-regulated kinase (ERK) signaling pathway in many different cell types. In this study, we demonstrated that endogenously produced uPA functions as a major determinant of the basal level of activated ERK in MDA-MB-231 breast cancer cells. When these cells were cultured in the presence of antibodies that block the binding of uPA to uPAR, the level of phosphorylated ERK decreased substantially. Furthermore, conditioned medium from MDA-MB-231 cells activated ERK in MCF-7 cells and this response was blocked by uPA-specific antibody. The mitogen-activated protein kinase kinase inhibitor, PD098059, decreased expression of uPA and uPAR in MDA-MB-231 cells. Thus, uPA and the uPAR-ERK signaling pathway form a positive feedback loop in these cells. When this feedback loop was disrupted with uPA- or uPAR-specific antibody, uPA mRNA-specific antisense oligodeoxynucleotides or PD098059, cell growth was inhibited and apoptosis was promoted, as determined by the increase in cytoplasmic nucleosomes and caspase-3 activity. Treating the cells simultaneously with PD098059 and uPA- or uPAR-specific antibody did not further promote apoptosis, compared with either reagent added separately, supporting the hypothesis that uPAR and ERK are components of the same cell growth/survival-regulatory pathway. The ability of uPA to signal through uPAR, maintain an elevated basal level of activated ERK and inhibit apoptosis represents a novel mechanism whereby the uPA-uPAR system may affect breast cancer progression in vivo.

scholarly journals The extracellular matrix of the lung and its role in edema formation

2007 ◽  
Vol 79 (2) ◽  
pp. 285-297 ◽  
Author(s):  
Paolo Pelosi ◽  
Patricia R.M. Rocco ◽  
Daniela Negrini ◽  
Alberto Passi
Keyword(s):  
Extracellular Matrix ◽  
Three Dimensional ◽  
Protective Role ◽  
Lung Edema ◽  
Type I ◽  
Matrix Remodeling ◽  
Edema Formation ◽  
Surface Receptors ◽  
Matrix Deposition ◽  
Extracellular Matrix Components

The extracellular matrix is composed of a three-dimensional fiber mesh filled with different macromolecules such as: collagen (mainly type I and III), elastin, glycosaminoglycans, and proteoglycans. In the lung, the extracellular matrix has several functions which provide: 1) mechanical tensile and compressive strength and elasticity, 2) low mechanical tissue compliance contributing to the maintenance of normal interstitial fluid dynamics, 3) low resistive pathway for an effective gas exchange, d) control of cell behavior by the binding of growth factors, chemokines, cytokines and the interaction with cell-surface receptors, and e) tissue repair and remodeling. Fragmentation and disorganization of extracellular matrix components comprises the protective role of the extracellular matrix, leading to interstitial and eventually severe lung edema. Thus, once conditions of increased microvascular filtration are established, matrix remodeling proceeds fairly rapidly due to the activation of proteases. Conversely, a massive matrix deposition of collagen fiber decreases interstitial compliance and therefore makes the tissue safety factor stronger. As a result, changes in lung extracellular matrix significantly affect edema formation and distribution in the lung.

Expression and localization of urokinase-type plasminogen activator receptor in bovine cumulus–oocyte complexes

Zygote ◽  
2015 ◽  
Vol 24 (2) ◽  
pp. 230-235 ◽  
Author(s):  
Daniela C. García ◽  
Dora C. Miceli ◽  
Gabriela Rizo ◽  
Elina V. García ◽  
Pablo A. Valdecantos ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Plasma Membrane ◽  
Plasminogen Activator ◽  
Cumulus Cells ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Pai 1

SummaryUrokinase-type plasminogen activator (uPA) is a serine protease involved in extracellular matrix remodeling through plasmin generation. uPA usually binds to its receptor, uPAR, which is anchored to the plasma membrane through a glycosylphosphatidylinositol anchor. uPA/uPAR binding increases proteolytic activity in the neighborhood of the cells containing uPAR and activates intracellular signaling pathways involved in extracellular matrix remodeling, cell migration and proliferation. The aim of this work was to study the expression of uPA, uPAR and plasminogen activator inhibitor-1 (PAI-1) in immature and in vitro matured bovine cumulus–oocyte complexes (COCs). uPA is only expressed in the cumulus cells of immature and in vitro matured COCs, while uPAR and PAI-1 are expressed in both the cumulus cells and the immature and in vitro matured oocytes. In addition, uPAR protein was localized by confocal microscopy in the plasma membrane of oocytes and cumulus cells of immature COCs. Results from this research led us to hypothesize that the uPA/uPAR interaction could cause the local production of uPA-mediated plasmin over oocyte and cumulus cell surface; plasmin formation could also be regulated by PAI-1.

Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors

2003 ◽  
Vol 70 ◽  
pp. 201-212 ◽  
Author(s):  
Hideaki Nagase ◽  
Keith Brew
Keyword(s):  
Three Dimensional ◽  
Therapeutic Interventions ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Structural Basis ◽  
Structural Elements ◽  
Ridge Structure ◽  
Extracellular Matrix Components ◽  
Metalloproteinase Inhibitors ◽  
The Matrix ◽  
A Disintegrin And Metalloproteinase

The tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of the matrix metalloproteinases (MMPs), enzymes that play central roles in the degradation of extracellular matrix components. The balance between MMPs and TIMPs is important in the maintenance of tissues, and its disruption affects tissue homoeostasis. Four related TIMPs (TIMP-1 to TIMP-4) can each form a complex with MMPs in a 1:1 stoichiometry with high affinity, but their inhibitory activities towards different MMPs are not particularly selective. The three-dimensional structures of TIMP-MMP complexes reveal that TIMPs have an extended ridge structure that slots into the active site of MMPs. Mutation of three separate residues in the ridge, at positions 2, 4 and 68 in the amino acid sequence of the N-terminal inhibitory domain of TIMP-1 (N-TIMP-1), separately and in combination has produced N-TIMP-1 variants with higher binding affinity and specificity for individual MMPs. TIMP-3 is unique in that it inhibits not only MMPs, but also several ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with thrombospondin motifs) metalloproteinases. Inhibition of the latter groups of metalloproteinases, as exemplified with ADAMTS-4 (aggrecanase 1), requires additional structural elements in TIMP-3 that have not yet been identified. Knowledge of the structural basis of the inhibitory action of TIMPs will facilitate the design of selective TIMP variants for investigating the biological roles of specific MMPs and for developing therapeutic interventions for MMP-associated diseases.

Urokinase type plasminogen activator and inhibitor type-1 plasma levels in colorectal cancer

2001 ◽  
Vol 120 (5) ◽  
pp. A599-A600 ◽  
Author(s):  
L HERSZENYI ◽  
F FARINATI ◽  
G ISTVAN ◽  
M PAOLI ◽  
G ROVERONI ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasminogen Activator ◽  
Plasma Levels ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Inhibitor Type

Structural Studies of Fibrinolysis by Electron and Light Microscopy

1999 ◽  
Vol 82 (08) ◽  
pp. 277-282 ◽  
Author(s):  
Yuri Veklich ◽  
Jean-Philippe Collet ◽  
Charles Francis ◽  
John W. Weisel
Keyword(s):  
Electron Microscopy ◽  
Light Microscopy ◽  
Plasminogen Activator ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Degradation Products ◽  
Molecular Model ◽  
Three Dimensional ◽  
Tissue Type ◽  
Type Plasminogen Activator

IntroductionMuch is known about the fibrinolytic system that converts fibrin-bound plasminogen to the active protease, plasmin, using plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator. Plasmin then cleaves fibrin at specific sites and generates soluble fragments, many of which have been characterized, providing the basis for a molecular model of the polypeptide chain degradation.1-3 Soluble degradation products of fibrin have also been characterized by transmission electron microscopy, yielding a model for their structure.4 Moreover, high resolution, three-dimensional structures of certain fibrinogen fragments has provided a wealth of information that may be useful in understanding how various proteins bind to fibrin and the overall process of fibrinolysis (Doolittle, this volume).5,6 Both the rate of fibrinolysis and the structures of soluble derivatives are determined in part by the fibrin network structure itself. Furthermore, the activation of plasminogen by t-PA is accelerated by the conversion of fibrinogen to fibrin, and this reaction is also affected by the structure of the fibrin. For example, clots made of thin fibers have a decreased rate of conversion of plasminogen to plasmin by t-PA, and they generally are lysed more slowly than clots composed of thick fibers.7-9 Under other conditions, however, clots made of thin fibers may be lysed more rapidly.10 In addition, fibrin clots composed of abnormally thin fibers formed from certain dysfibrinogens display decreased plasminogen binding and a lower rate of fibrinolysis.11-13 Therefore, our increasing knowledge of various dysfibrinogenemias will aid our understanding of mechanisms of fibrinolysis (Matsuda, this volume).14,15 To account for these diverse observations and more fully understand the molecular basis of fibrinolysis, more knowledge of the physical changes in the fibrin matrix that precede solubilization is required. In this report, we summarize recent experiments utilizing transmission and scanning electron microscopy and confocal light microscopy to provide information about the structural changes occurring in polymerized fibrin during fibrinolysis. Many of the results of these experiments were unexpected and suggest some aspects of potential molecular mechanisms of fibrinolysis, which will also be described here.

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