The Receptor for Urokinase-type Plasminogen Activator Is Not Essential for Mouse Development or Fertility

Bugge, Thomas H.; Suh, Theodore T.; Flick, Matthew J.; Daugherty, Cynthia C.; Rømer, John; Solberg, Helene; Ellis, Vincent; Danø, Keld; Degen, Jay L.

doi:10.1074/jbc.270.28.16886

Cited by 211 publications

(154 citation statements)

References 64 publications

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“…The data are expressed as the mean tumor weight+the standard error of the mean. *P50.02 and **P50.003, Wilcoxon rank-sum test, two-tailed Tumor produced Plg activator and Plg cooperate to suppress macrophage accumulation and promote angiogenesis independent of stromal uPAR Macrophages express Plg activator and uPAR and are dependent on uPAR for productive cell surface plasmin generation (Bugge et al, 1995b). uPA7/7/tPA7/7 mice have no macrophage-associated plasmin formation.…”

Section: Plg Promotes Tumor Growth and Vascularization And Suppressesmentioning

confidence: 99%

Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages

et al. 2002

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The specific functions of plasminogen, stromal plasminogen activator, stromal plasminogen activator receptor, and stromal plasminogen activator inhibitor in the progression of the murine soft tissue sarcoma, T241 were investigated. Negation of plasminogen to the tumor blunted the orthotopic growth of the sarcoma in syngeneic mice. The reduced tumor growth was associated with a dramatic increase in tumor-infiltrating F4/80-positive macrophages and a diminution of vessel density, but not with obvious differences in fibrin and collagen deposition, or invasiveness of the tumor. Ablation of plasminogen activation by the tumor stroma only modestly impaired the prolonged growth of the sarcoma, suggesting that tumor cell-produced plasminogen activator is sufficient to mediate productive plasminogen activation. Plasminogen facilitated sarcoma progression, angiogenesis, and suppression of macrophage infiltration in the absence of either stromal urokinase plasminogen activator receptor or stromal plasminogen activator inhibitor. These data demonstrate that tumor cell-produced plasminogen activator and host plasminogen cooperate to facilitate soft tissue sarcoma growth and suppress the accumulation of tumor-infiltrating macrophages.

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Section: Plg Promotes Tumor Growth and Vascularization And Suppressesmentioning

confidence: 99%

Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages

et al. 2002

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“…However, the role of plasmin in signal transduction-mediated cytokine expression during pathologic processes, especially bacterial arthritis, remains to be determined. Mice with deficiencies in different components of the PA system provide useful model systems for functional studies on the role of the PA system in vivo (6,(19)(20)(21). To investigate the roles that plasmin may play in S aureus-induced arthritis, we used a mouse model of bacterial arthritis whereby 1 ϫ 10 6 colony-forming units (CFU) of S aureus was injected into the knee joints.…”

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confidence: 99%

Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus–induced arthritis

Guo¹,

Li²,

Hagström³

et al. 2008

Arthritis & Rheumatism

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Objective. To assess the functional roles of plasmin in a murine model of Staphylococcus aureus-induced bacterial arthritis.Methods. Bacterial arthritis was induced in plasminogen-deficient (Plg -/-) and wild-type (Plg ؉/؉ ) littermates by local injection of 1 ؋ 10 6 colony-forming units of S aureus into the knee joints. Human plasminogen was administered to Plg -/-mice on days 0-7 or days 7-14. Antibiotic treatment was administered to Plg -/-mice on days 7-14. Bacteria counts and histologic, immunohistochemical, and Western blot analyses were performed.Results. In Plg ؉/؉ mice, S aureus counts had declined within 2 days, and by day 28 the bacteria had been completely eliminated. However, S aureus was still detectable in all injected joints from Plg -/-mice, and bacteria counts were 27 times higher than the amount injected on day 0. The extent of macrophage and neutrophil recruitment to the infected joints was comparable for Plg ؉/؉ and Plg -/-mice on days 1, 7, and 14. The activation of these inflammatory cells appeared to be impaired in Plg -/-mice, however. Treatment of Plg -/-mice with antibiotic (cloxacillin) resulted in successful killing of the bacteria, but the necrotic tissue remained in the infected joints. When human plasminogen was given intravenously to Plg -/-mice daily for 7 days, bacterial clearance was greatly improved as compared with their untreated counterparts, and the amount of necrotic tissue in the joint cavity was dramatically reduced. The expression of interleukin 6 (IL-6) and IL-10 was higher in Plg ؉/؉ mice than in Plg -/-mice during bacterial arthritis.Conclusion. Our findings indicate that plasmin plays a pluripotent role in protecting against S aureusinduced arthritis by activating inflammatory cells, killing bacteria, removing necrotic tissue, and enhancing cytokine expression.Staphylococcus aureus is the microorganism most frequently associated with bacterial arthritis (1,2), which results in synovial inflammation, cartilage and bone destruction, and eventually, joint deformity (3). The plasminogen activator (PA) system is a general proteolytic system that has been suggested to play an important role in the development of different types of arthritis (4-6). Plasminogen can be activated to the broadspectrum protease plasmin by either of the 2 physiologic PAs, tissue-type PA (tPA) or urokinase-type PA (uPA). In addition to its function in fibrinolysis, plasmin(ogen) plays a role in degradation of the extracellular matrix (ECM) and in tissue remodeling during many physiologic and pathologic processes, such as wound healing (7), tumor cell invasion, angiogenesis, and rheumatoid arthritis (RA) (8). There is some evidence that plasmin can also induce proinflammatory responses independently of its proteolytic properties (9).A number of pathogenic microorganisms have been shown to bind plasminogen (10-12). The subsequent activation of plasminogen to plasmin may contribute to the virulence of these microorganisms (13). However, during bacterial arthritis, plasmin may also be of importance...

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“…Hence abolishment of single components of the plasminogen activation system, i.e. uPA (13), tPA (13), and uPAR (14,15), by gene targeting does not affect the viability of the homozygous knock-out animals as they by and large exhibit normal phenotypes with respect to growth, reproduction, and survival. In contrast, mice with combined deficiency in uPA and tPA are characterized by retarded growth, reduced fertility, and shortened life span (13).…”

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confidence: 99%

Antibody-mediated Targeting of the Urokinase-type Plasminogen Activator Proteolytic Function Neutralizes Fibrinolysis in Vivo

Lund

Jögi

Rønø

et al. 2008

Journal of Biological Chemistry

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Urokinase-type plasminogen activator (uPA) plays a central role in tissue remodeling processes. Most of our understanding of the role of uPA in vivo is derived from studies using genetargeted uPA-deficient mice. To enable in vivo studies on the specific interference with uPA functionality in mouse models, we have now developed murine monoclonal antibodies (mAbs) directed against murine uPA by immunization of uPA-deficient mice with the recombinant protein. Guided by enzyme-linked immunosorbent assay, Western blotting, surface plasmon resonance, and enzyme kinetic analyses, we have selected two highly potent and inhibitory anti-uPA mAbs (mU1 and mU3). Both mAbs recognize epitopes located on the B-chain of uPA that encompasses the catalytic site. In enzyme activity assays in vitro, mU1 blocked uPA-catalyzed plasminogen activation as well as plasmin-mediated pro-uPA activation, whereas mU3 only was directed against the first of these reactions. We additionally provide evidence that mU1, but not mU3, successfully targets uPAdependent processes in vivo. Hence, systemic administration of mU1 (i) rescued mice treated with a uPA-activable anthrax protoxin and (ii) impaired uPA-mediated hepatic fibrinolysis in tissue-type plasminogen activator (tPA)-deficient mice, resulting in a phenotype mimicking that of uPA;tPA double deficient mice. Importantly, this is the first report demonstrating specific antagonist-directed targeting of mouse uPA at the enzyme activity level in a normal physiological process in vivo.

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The Receptor for Urokinase-type Plasminogen Activator Is Not Essential for Mouse Development or Fertility

Cited by 211 publications

References 64 publications

Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages

Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages

Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus–induced arthritis

Antibody-mediated Targeting of the Urokinase-type Plasminogen Activator Proteolytic Function Neutralizes Fibrinolysis in Vivo

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