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  • 1
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    Impact of Smad3 loss of function on scarring and adhesion formation during tendon healing
    Wiley ; 2011
    In:  Journal of Orthopaedic Research Vol. 29, No. 5 ( 2011-05), p. 684-693
    Details
    In: Journal of Orthopaedic Research, Wiley, Vol. 29, No. 5 ( 2011-05), p. 684-693
    Abstract: Studies were performed evaluating the role of Smad3, a transcription factor mediating canonical TGF‐β signaling, on scarring and adhesion formation using an established flexor digitorum longus (FDL) tendon repair model. In unoperated animals the metatarsophalangeal (MTP) range of motion (ROM) was similar in Smad3 −/− and wild‐type (WT) mice while the basal tensile strength of Smad3 −/− tendons was significantly (39%) lower than in WT controls. At 14 and 21 days following repair Smad3 −/− MTP ROM reached approximately 50% of the basal level and was twice that observed in WT tendon repairs, consistent with reduced adhesion formation. Smad3 −/− and WT maximal tensile repair strength on post‐operative day 14 was similar. However, Smad3 −/− tendon repairs maximal tensile strength on day 21 was 42% lower than observed in matched WT mice, mimicking the relative decrease in strength observed in Smad3 −/− FDL tendons under basal conditions. Histology showed reduced “healing callus” in Smad3 −/− tendons while quantitative PCR, in situ hybridization, and immunohistochemistry showed decreased col3a1 and col1a1 and increased MMP9 gene and protein expression in repaired Smad3 −/− tendons. Thus, Smad3 −/− mice have reduced collagen and increased MMP9 gene and protein expression and decreased scarring following tendon FDL tendon repair. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:684–693, 2011
    Type of Medium: Online Resource
    ISSN: 0736-0266 , 1554-527X
    URL: Issue
    URL: Article
    DOI: 10.1002/jor.v29.5
    DOI: 10.1002/jor.21235
    Language: English
    Publisher: Wiley
    Publication Date: 2011
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  • 2
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    Factor XIII activity mediates red blood cell retention in venous thrombi
    American Society for Clinical Investigation ; 2014
    In:  Journal of Clinical Investigation Vol. 124, No. 8 ( 2014-8-1), p. 3590-3600
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 124, No. 8 ( 2014-8-1), p. 3590-3600
    Type of Medium: Online Resource
    ISSN: 0021-9738
    URL: Article
    URL: Article
    DOI: 10.1172/JCI75386
    DOI: 10.1172/JCI75386DS1
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2014
    detail.hit.zdb_id: 2018375-6
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  • 3
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    Thrombin Supports Colitis and Colitis-Associated Cancer Pathogenesis
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2237-2237
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2237-2237
    Abstract: Abstract 2237 Chronic inflammation has been recognized as a major factor in the development and progression of multiple cancers. A prime example of this is the strong association between colitis and colon cancer. However, the specific factors that regulate disadvantageous immune processes in the context of inflammation-associated cancers remain poorly defined. Growing evidence suggests that hemostatic system components, traditionally associated with the maintenance of vascular integrity and prevention of blood loss, also directly regulate inflammatory processes. Furthermore, thrombin and several thrombin targets (e.g., PARs, fibrinogen, factor XIII) have been shown to regulate tumor cell proliferation and apoptosis, support metastasis, and protect tumor cells from innate immune surveillance mechanisms in other experimental contexts. A logical extension of these findings is the hypothesis that thrombin, as a master regulator of both inflammatory processes and tumor cell biology, is a major determinant of the progression of inflammation-driven cancers such as colitis-associated colon cancer (CAC). To test this hypothesis, we induced CAC in mice carrying prothrombin levels 50% of normal (fII+/−) and WT mice in parallel using an established two step protocol consisting of azoxymethane (AOM) and dextran sodium sulfate (DSS) exposure. The modest diminution in prothrombin levels imposed by the fII+/− genotype resulted in a dramatic diminution in the number of colonic adenomas formed after AOM/DSS challenge relative to WT mice. In order to determine if the diminution in adenoma formation observed in fII+/− mice was coupled to thrombin function, wildtype mice challenged with AOM/DSS were treated with daily i.p. injections of hirudin, a direct thrombin inhibitor, or saline carrier. Similar to the finding in mice with a genetically-imposed diminution in circulating prothrombin, hirudin treatment significantly blunted adenoma formation. To determine if reduction of thrombin generation improved the inflammation preceding the development of colonic adenomas, we used a novel, highly-specific factor XI antisense oligonucleotide “gapmer” (ISIS Pharmaceuticals) to inhibit hepatic factor XI synthesis prior to DSS challenge. Gapmer-mediated diminution of fXI levels to ∼15% of normal resulted in a dramatic improvement in colitis related symptoms. Gapmer-treated mice had less intestinal bleeding and weight loss associated with DSS challenge relative to mice treated with a control oligonucleotide. Consistent with these gross observations, microscopic analyses of colonic tissue showed that fXI gapmer treatment significantly limited mucosal ulceration. Factor XI gapmer treatment also significantly diminished local levels of several inflammatory cytokines known to play a role in colon cancer progression (i.e., IL-6, IL-1β, IL-12). These results demonstrate that thrombin is a crucial driver of the pathogenesis of colitis-associated colon cancer and suggest that therapies directed at thrombin or thrombin generation could treat or prevent inflammation-driven colon cancer. As pathological inflammation has been estimated to account for as many as 1 in 5 cancer-related deaths, thrombin-directed therapies could have broad applicability to multiple malignancies. Disclosures: Mullins: Baxter: Consultancy. Monia:Isis Pharmaceuticals: Employment. MacLeod:Isis Pharmaceuticals: Employment. Revenko:Isis Pharmaceuticals: Employment. Palumbo:Novo Nordisk: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2237.2237
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 4
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    PAR-1 Is a Context Dependent Determinant of Colitis and Colitis-Associated Cancer.
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 2221-2221
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2221-2221
    Abstract: Abstract 2221 Increased thrombin generation and hypercoagulability are prominent features of inflammatory colitis and previous studies from our laboratory have suggested that thrombin-mediated proteolysis is a driver of both colitis and colitis-associated colon cancer (CAC). However, the downstream thrombin targets important in these disease processes have not been fully defined. Based on studies showing that the protease activated receptor-1 (PAR-1) can contribute to both inflammatory pathologies and cancer progression in other settings, we hypothesized that PAR-1 is a significant determinant of colitis and CAC. To test this hypothesis, we induced colitis in PAR-1−/− and control mice using intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Consistent with the concept that PAR-1 is a modifier of colitis pathobiology, PAR-1−/− mice lost significantly less weight than WT mice challenged in parallel. Furthermore, multiple inflammatory cytokines known to drive colitis pathology, including IL-6, TNFa, and MIP-1α, were significantly diminished in PAR-1−/− mice. However, histological analyses of colonic tissue revealed similar degrees of inflammatory cell infiltration, crypt abscesses, and mucosal hyperplasia in both genotypes. In order to explore the role of PAR-1 in the more complex process of inflammation-driven colon cancer pathogenesis, we induced CAC in PAR-1−/− and WT mice using a two step protocol consisting of azoxymethane (AOM) and dextran sodium sulfate (DSS) exposure. In contrast to findings in the setting of TNBS challenge, PAR-1−/− mice challenged with DSS developed, not less, but more severe clinical signs of colitis, including wasting and severe diarrhea. More detailed comparative studies of DSS-challenged PAR-1−/− and control mice established that PAR-1-deficient animals developed significantly greater immunological and histopathological evidence of colitis, including elevated IL-6 and MIP-1α levels in colonic tissue and increased edema, ulceration, crypt loss, and inflammatory cell infiltration. Consistent with the more severe antecedent colitis, PAR-1−/− mice challenged with AOM/DSS developed significantly larger adenomas than WT mice challenged and evaluated in parallel. Thus, the impact of PAR-1 on colitis appears to be context-dependent and the distinct outcomes in TNBS- and DSS-challenged mice are likely to stem from the different mechanisms by which these agents induce colitis. TNBS is thought to haptenate colonic mucosal proteins inducing a T cell-mediated colitis akin to human Crohn's disease. In contrast, DSS directly intoxicates colonic crypt epithelia, resulting in loss of barrier function and translocation of colonic microflora, leading to a primarily innate immune-driven colitis sharing many features with ulcerative colitis. A major challenge in dissecting the precise mechanisms coupling PAR-1 to colitis is the fact that PAR-1 is expressed on multiple cell types that can influence colitis and CAC in distinct ways, including immune cells, endothelial cells and colonic mucosa. Therefore, we recently generated mice carrying a conditional “floxed” PAR-1 allele. We interbred these animals with mice expressing Cre recombinase in either colonic epithelia or the hematopoietic/endothelial compartment. Preliminary studies revealed that loss of PAR-1 expression in the hematopoietic/endothelial compartments, but not the colonic epithelia, recapitulates the more severe DSS-induced weight loss and mucosal damage observed in constitutionally PAR-1-deficient mice. These results suggest that PAR-1 activation in either immune cells and/or endothelial cells limits colitis severity in this experimental context. Taken together, these data show that PAR-1 contributes to the pathogenesis of inflammatory colitis and CAC, but the precise contribution is dependent on the underlying insult and disease pathway. Analyses in mice carrying a conditional PAR-1 allele should prove invaluable for dissecting the precise mechanisms coupling PAR-1 to inflammatory bowel disease. Disclosures: Palumbo: Novo Nordisk Corporation: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.2221.2221
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 5
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    Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptor
    Oxford University Press (OUP) ; 2012
    In:  Human Molecular Genetics Vol. 21, No. 9 ( 2012-5-1), p. 1989-2004
    Details
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 21, No. 9 ( 2012-5-1), p. 1989-2004
    Type of Medium: Online Resource
    ISSN: 1460-2083 , 0964-6906
    URL: Article
    DOI: 10.1093/hmg/dds012
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    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2012
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  • 6
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    Fibrin Crosslinking Is Required For Retention Of Red Blood Cells In Venous Thrombi,
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 451-451
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 451-451
    Abstract: Venous thrombi contain high levels of red blood cells (RBC) and fibrin, but little is known about the mechanisms regulating venous thrombus formation and composition. Fibrin acts as a scaffold for leukocytes and platelets that mediate thrombus formation, and cross-linked fibrin networks promote clot stability via their extraordinary extensibility and elasticity. Previous studies have shown that a region of the fibrinogen γ-chain (residues γ390-396) is critical for engagement of the leukocyte integrin receptor αMβ2. Mice expressing a mutant form of fibrinogen with residues 390-396 mutated to a series of alanines (termed Fibγ390-396A) exhibit normal fibrin polymerization and normal hemostasis. However, Fibγ390-396A mice exhibit blunted inflammatory responses and protection from the development of numerous inflammatory diseases (e.g., arthritis, neuroinflammatory disease, colitis). In this study, we analyzed the role of this region of fibrinogen in a stasis-induced model of venous thrombosis. Surprisingly, following inferior vena cava ligation – a model that produces thrombi independent of leukocyte tissue factor activity – Fibγ390-396A mice had 50% smaller thrombi than wild type (WT) mice (9.7±1.3 vs 19.5±1.7 mg, P 〈 0.0003). Reduced thrombus weight was not due to reduced thrombin generation (i.e., TAT levels), and total neutrophil, platelet, and fibrin content within thrombi were similar between groups. Strikingly, Fibγ390-396A thrombi had significantly fewer RBCs than WT thrombi (16.0±4.1 vs 52.9±5.8 arbitrary units [AU], P 〈 0.0001), and thrombus RBC content correlated positively (R=0.90) and significantly (P 〈 0.001) with overall thrombus weight. To determine the mechanism of decreased RBC presence in thrombi from Fibγ390-396A mice, we developed an ex vivo whole blood clot retraction assay. Interestingly, although retraction of platelet-rich plasma clots was indistinguishable for Fibγ390-396A and WT mice (91±1 vs 92±1 %), retraction of whole blood clots resulted in dramatically reduced RBC retention (37.0±8.4 vs 79.0±8.0 % of initial RBCs, P 〈 0.03) and smaller clots (11.6±1.6 vs 53.8±3.6 mg, P 〈 0.003) for Fibγ390-396A mice compared to WT. Reconstitution experiments showed the mechanism of decreased RBC retention was not due to abnormal RBC function. Microfluidic-based adhesion analyses indicated RBCs adhered similarly to both Fibγ390-396A and WT purified fibrinogen (65.7±6.4 vs 76.7±14.8 % cell adhesion, respectively, P=0.55), indicating that RBC extrusion did not result from decreased RBC binding to Fibγ390-396A clots. To test the hypothesis that the Fibγ390-396A mutation disrupts a specific interaction with the fibrin-stabilizing transglutaminase, factor XIII (FXIII), we analyzed levels of FXIII that co-precipitated with WT and Fibγ390-396A fibrinogen. Interestingly, despite normal circulating levels of FXIII in Fibγ390-396A mice, FXIII co-precipitated with WT fibrinogen, but not with Fibγ390-396A fibrinogen. Compared to WT, plasma clots from Fibγ390-396A mice exhibited slower FXIII activation (58.3±19.2 vs 12.2±2.5 AU/min [x10-3], P 〈 0.05) and consequently, slower fibrin crosslinking (γ-γ dimers: 114±14.2 vs 19.5±2.5 AU/min [x10-3], P 〈 0.0001; α polymers: 278±52 vs 46.1±11.4 AU/min [x10-3], P 〈 0.002) and reduced elastic modulus (14.1±0.2 vs 7.8±0.6 G’ [Kd/sec], P 〈 0.0005). Provocatively, whole blood from FXIII-deficient mice and humans phenocopied Fibγ390-396A clots, with reduced RBC retention following clot retraction. Taken together, these studies suggest a critical, yet previously un-described, role for FXIII in mediating RBC retention within clots. Further, these data identify critical residues in fibrinogen that mediate FXIII activation and fibrin crosslinking, and reveal that FXIII-mediated fibrin crosslinking is required for the retention of RBCs in venous thrombi. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.451.451
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 7
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    Plasminogen Mediates Both Positive and Negative Effects on Disease Severity in a Mouse Model of TNFα-Driven Arthritis
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 854-854
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 854-854
    Abstract: Abstract 854 Rheumatoid arthritis is a chronic inflammatory disease of joint tissue wherein dysregulated, robust hemostatic system activity is a consistent pathological feature. Increased local expression of fibrinolytic system components (i.e., plasminogen activators) and accumulation of fibrin degradation products within arthritic joints suggest that plasmin(ogen) may directly or indirectly participate in joint tissue inflammatory/degradative processes. To test the hypothesis that plasmin-mediated proteolysis drives local events in arthritis pathogenesis, we examined the effect(s) of plasminogen deficiency (Plg−) on TNFα-driven arthritis in Tg197 transgenic mice that spontaneously develop a chronic, erosive form of polyarthritis. Comparative macroscopic analysis of the distal joints (fore- and hind-paws) from 10-week old mice revealed that plasminogen deficiency resulted in significantly elevated arthritic disease compared to plasminogen-sufficient control animals. Consistent with overt macroscopic disease, evaluation of distal joint sections using a semi-quantitative histopathological scoring system confirmed that Plg− Tg197 mice developed significantly more advanced arthritic disease relative to controls. Typical disease features included extensive synovial hyperplasia, inflammatory cell infiltration, pannus formation, cartilage degradation and bone loss. Remarkably, histological examination of the proximal joints (knees) from the same set of animals revealed that Plg− Tg197 mice developed markedly diminished arthritic disease relative to controls, suggesting that the impact of plasminogen on the progression of arthritis is dependent on anatomical location. Given that fibrin is a primary substrate for plasmin-mediated proteolysis, we examined joint tissue for evidence of fibrin deposition by immunohistochemistry. In distal joints of the paws, Plg− Tg197 mice displayed robust fibrin deposition throughout the hyperplastic synovial tissue and along the articular surfaces exhibiting evidence of cartilage degradation. The degree of fibrin staining in the distal paw joints appeared to correlate with the disease severity (i.e., more extensive fibrin staining in Plg− Tg197 mice with advanced arthritic disease). Intriguingly, fibrin deposition was also observed in the proximal knee joints of Plg− Tg197 transgenic mice, despite the limited arthritis severity. To determine whether fibrin was the plasmin substrate mediating the distinct differences in TNFα-driven arthritis severity at one or both of the anatomical locations examined (i.e., paw joints or knee joints) in Plg− Tg197 mice, fibrinogen deficiency was superimposed on the Plg− background generating mice with combined plasminogen and fibrinogen deficiencies (e.g., Plg−/Fib− mice). Remarkably, comparative macroscopic as well as microscopic analyses revealed that the arthritis phenotypes were reversed in both the paw and the knee joints of Plg−/Fib− Tg197 mice relative to Plg−/Fib+ Tg197 mice. Together, these data strongly suggest that fibrin is a dominant plasmin target that contributes to arthritis pathogenesis. A thorough understanding of the precise mechanisms underlying the plasminogen-dependent, location-specific differences in arthritis progression will likely provide valuable insight into novel therapeutic strategies to effectively treat inflammatory arthritis. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.854.854
    RVK:
    XA 33000
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 8
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    Host Fibrinogen and the S. Aureus-Encoded Procoagulant Vwbp Are Context-Dependent Determinants of Bacterial Virulence.
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1152-1152
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1152-1152
    Abstract: Abstract 1152 Microbial pathogens frequently express bacterial products that are specifically designed to engage hemostatic system components in their vertebrate hosts. Staphylococcus aureus has evolved a particularly impressive repertoire of factors to control fibrin deposition, dissolution, and binding, including two bacterial products that form proteolytically active procoagulant complexes with prothrombin, staphylocoagulase (Coa) and von Willebrand factor binding protein (vWbp). These findings support the working hypothesis that hemostatic factors, in general, and fibrinogen, in particular, are likely to be important determinants of S. aureus virulence/host defense. To directly explore the role of fibrin(ogen) in host inflammatory/antimicrobial processes, a comparative analysis of bacterial clearance was done in control and fibrinogen-deficient mice in the context of S. aureus peritonitis. Control mice challenged with 109 CFU of S. aureus were found to efficiently clear S. aureus within the peritoneal cavity and eliminated ∼99.5% of bacterial CFUs within 20 minutes, whereas fibrin(ogen)-deficient mice exhibited little capacity to clear the microbe, even after several hours. Consistent with these findings, fibrinogen-deficient mice challenged with S. aureus peritonitis also exhibited a poor survival profile relative to control animals. More detailed studies to define the mechanism(s) underlying the rapid, fibrin(ogen)-dependent clearance of S. aureus have thus far excluded a critical contribution of host T cells, B cells, neutrophils, immunglobulins, complement, toll-like receptor signaling pathways, and the bacterial fibrinogen receptor clumping factor A (ClfA). However, mice carrying low levels of circulating prothrombin or expressing a mutant form of fibrinogen that cannot be converted to fibrin, exhibited a profound defect in S. aureus clearance following i.p. infection, suggesting a central role for fibrin polymer in the implementation of an effective antimicrobial program. Although fibrin formation is necessary, it is not sufficient for efficient bacterial clearance; Fibγ390-396A mice retaining full clotting function, but lacking the leukocyte integrin Mac-1 binding motif, also exhibit an impediment in bacterial clearance relative to wild-type mice. Complementary studies of S. aureus mutants deficient in bacterial procoagulants indicate that vWbp, but not Coa, is a fundamental determinant of bacterial clearance in this peritonitis model. Remarkably, bacterial procoagulant vWbp is distinctly counter-productive to the microbe in the context of peritonitis and supports the rapid, fibrin(ogen)-dependent clearance of intraperitoneal S. aureus. Based on findings indicating that host fibrinogen and bacterial factors that engage fibrin(ogen) support S. aureus virulence in other infection settings, the present findings suggest that host hemostatic factors and the bacterial procoagulant vWbp are likely to be context-dependent determinants of bacterial virulence. A better understanding of the interactions between bacterial proteins and host hemostatic factors, as well as interactions between the host hemostatic and inflammatory/immune systems, may well reveal novel therapeutic approaches for limiting microbial infections and sepsis. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1152.1152
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 9
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    Mice Deficient in Urokinase-Type Plasminogen Activator (uPA) or uPA Receptor Develop Significantly Diminished Collagen-Induced Arthritis
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 580-580
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 580-580
    Abstract: Rheumatoid arthritis (RA) is a common and debilitating autoimmune disease characterized by chronic inflammation, synovial hyperplasia, edema, cartilage and bone erosion and loss of joint function. Increasing evidence suggests that the plasminogen activation (PA) system plays a fundamental role in the mechanisms mediating inflammatory joint disease pathogenesis. However, analysis of the precise contribution of PA system components to arthritis pathogenesis has been complicated by the use of gene-targeted mice on non-susceptible genetic backgrounds or experimental models that simultaneously induce wound trauma in conjunction with arthritis induction. To rigorously define the contribution of the urokinase-type plasminogen activator system to arthritis pathogenesis, previously generated genetic deficiencies in both uPA and uPA receptor (uPAR) were inbred for 7 generations (99% inbred) to the well-characterized, collagen-induced arthritis (CIA)-susceptible strain, DBA/1J. Our results indicate a near complete amelioration of joint disease in uPA-deficient mice that was also observed in uPAR-deficient mice. Limited disease development in both uPA- and uPAR-deficient mice correlated with significantly reduced local mRNA levels of key inflammatory mediators (e.g., TNFα, IL-1β, and IL-6) in these animals. To determine if development of inflammatory joint disease in CIA-challenged mice was dependent on the expression of uPAR by non-hematopoietic- or hematopoietic-derived cells, reciprocal bone marrow transplant studies were performed. Mice in which uPAR deficiency was limited to the bone marrow compartment elicited significantly reduced macroscopic and histopathological disease in the paws and knees compared to wild-type mice or mice in which only hematopoietic-derived cells express uPAR. Our results are the first to report in the context of the highly CIA susceptible DBA/1 background that both uPA and uPAR are key determinants of inflammatory joint disease pathogenesis. Furthermore, our findings indicate a fundamental role for uPAR expression by hematopoietic cells in driving arthritis incidence and progression. Thus, these findings suggest that cell-surface associated uPA/uPAR-mediated proteolysis and/or uPAR-mediated signaling events from bone-marrow derived cells are important in promoting inflammatory joint disease, and that disrupting this key proteolytic/signaling system may provide a novel therapeutic strategy to limit clinical arthritis. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.580.580
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 10
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    Fibrin(ogen)-Independent Role of Plasminogen Activators in Acetaminophen-Induced Liver Injury
    Elsevier BV ; 2012
    In:  The American Journal of Pathology Vol. 180, No. 6 ( 2012-06), p. 2321-2329
    Details
    In: The American Journal of Pathology, Elsevier BV, Vol. 180, No. 6 ( 2012-06), p. 2321-2329
    Type of Medium: Online Resource
    ISSN: 0002-9440
    URL: Article
    DOI: 10.1016/j.ajpath.2012.02.011
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
    detail.hit.zdb_id: 1480207-7
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