Plasminogen activators and their inhibitors in synovial fluids from normal, osteoarthritis, and rheumatoid arthritis knees.

Belcher, Carolyn; Fawthrop, Fiona; Bunning, R.A.D.; Doherty, Michael

doi:10.1136/ard.55.4.230

Cited by 55 publications

(39 citation statements)

References 27 publications

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“…In previous studies, the expression of IL-17F, PAs, and PAI-1 increased in RA synovial tissue 11,25) . However, the effects of IL-17F on PAs and PAI-1 expression were not reported in the synovial tissue.…”

Section: Discussionmentioning

confidence: 99%

“…We also found that nicotine promotes extracellular matrix destruction by increasing tPA expression in human osteoblastic Saos-2 cells 23) , and that nicotine and lipopolysaccharide (LPS) contribute to bone resorption by increasing tPA production in osteoblasts 24) . In studies of RA and cartilage, it was reported that concentrations of tPA, uPA, and PAI-1 in synovial fluids are significantly higher in RA patients 25) and that IL-1 increases the expression of tPA, uPA, and PAI-1 in chondrocytes 26,27) . However, the effects of IL-17F on cartilage matrix turnover via the plasminogen/plasmin pathway are unclear.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-17F Down-Regulates the Plasminogen/Plasmin Pathway in Chondrocytes

Tanigawa

Kawato

Aida

et al. 2011

J. Hard Tissue Biology.

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Interleukin-17 (IL-17) is a proinflammatory cytokine involved in autoimmune diseases such as rheumatoid arthritis (RA). IL-17 consists of six ligands that signal through five receptors (IL-17Rs). Serine proteinases, such as plasmin and plasminogen activators (PAs), as well as matrix metalloproteinases (MMPs) degrade the extracellular matrix during cartilage remodeling.In contrast, plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of PAs, forms a complex with PA to inhibit plasmin production. In the present study, we examined the effect of IL-17F on the plasminogen/plasmin pathway in cartilage using human articular chondrocytes. We evaluated the effects of IL-17F on the expression of tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), PAI-1, and cyclooxygenases (COXs), as well as on the production of prostaglandin E 2 (PGE 2 ). We also examined the indirect effects of PGE 2 on the above IL-17F-induced/ reduced components using NS-398, a specific inhibitor of COX-2 activity. Cells were cultured with or without IL-17F in the presence or absence of NS-398 for up to 28 days. mRNA and protein expression levels of PAs, PAI-1, and COXs were determined using real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. PGE 2 production was determined by ELISA. The addition of IL-17F increased the expression of PAI-1 and COX-2, as well as the production of PGE 2 , whereas uPA and COX-1 expression decreased and tPA expression was unaffected. NS-398 did not block the reducing/stimulating effects of IL-17F on the expression of COX-1 and COX-2. In contrast, NS-398 may be, in part, responsible for IL-17F-induced/reduced uPA and PAI-1 expression. Our results suggest that IL-17F suppresses the plasminogen/ plasmin pathway by increasing PAI-1 expression and decreasing uPA expression in chondrocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interleukin-17F Down-Regulates the Plasminogen/Plasmin Pathway in Chondrocytes

Tanigawa

Kawato

Aida

et al. 2011

J. Hard Tissue Biology.

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“…In 1996, Belcher et al reported that synovial fluid levels of suPAR were raised in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) as compared to healthy controls [77]. Since then, uPAR and suPAR have been investigated both in humans and in animal models of OA [77][78][79][80][81], RA [26,77,78,80,[82][83][84][85][86][87][88], gouty arthritis [89], and ankylosing spondylitis [90].…”

Section: Supar As a Biomarker In Sle And Other Rheumatic Diseasesmentioning

confidence: 99%

“…Since then, uPAR and suPAR have been investigated both in humans and in animal models of OA [77][78][79][80][81], RA [26,77,78,80,[82][83][84][85][86][87][88], gouty arthritis [89], and ankylosing spondylitis [90]. There are also observations on involvement of the uPAR system in systemic sclerosis [91][92][93] and Behçet's disease [94].…”

Section: Supar As a Biomarker In Sle And Other Rheumatic Diseasesmentioning

confidence: 99%

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

Enocsson¹,

Sjöwall²,

Wetterö³

2015

Clinica Chimica Acta

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The expression of uPAR is mainly regulated by growth factors and pro-inflammatory cytokines like basic fibroblast growth factor, epidermal growth factor, tumor necrosis factor, interleukin ( suPAR as a clinical marker of inflammation and organ damagePlasma membrane expression of uPAR as well as the levels of circulating suPAR have been investigated in relation to a broad range of conditions and suPAR has been referred to as a "molecular crystal ball" due to its prognostic value in diseases like tuberculosis, HIV, sepsis and cancer [2,6,13,26,58,59]. Further, it has been reported that it reflects overall immune activation and systemic inflammation [2]. suPAR has also emerged as a potential biomarker of fibrosis in chronic liver diseases of diverse etiology [10,11,[60][61][62].Recently, suPAR attracted significant attention in primary focal segmental glomerulosclerosis (FSGS). data from this pilot study revealed significantly higher suPAR levels among patients with moderately or highly elevated SDI after study inclusion, compared to patients without SDI increase (Figure 2).Furthermore, there were higher death rates among patients in the two groups with SDI increase (Figure 2). However, it is well known that present organ damage predicts further organ damage [17,100], and thus, adjustment for SDI at baseline should be performed to reduce the risk of bias. A stepwise linear multiple regression analysis was therefore performed to evaluate the impact of suPAR on future SDI increase. After adjusting for age, sex and SDI at study inclusion, we found suPAR levels to have a significant impact on future SDI increase (p = 0.005, standardized β = 0.20) whereas SDI at study inclusion was excluded from the model. Since recent studies have revealed an inverse correlation between serum suPAR and glomerular filtration [67,68,96], we also included estimated glomerular filtration (eGFR) (calculated by the 4-variable Modification of Diet in Renal Disease StudyGroup formula [101]) in the analysis, but eGFR was not retained in the model. From these results, we suggest that suPAR can actually predict organ damage independent of present SDI score or eGFR, but that a prospective study examining the association between suPAR levels at the time of diagnosis with future SDI would be preferable.In line with these findings, elevated suPAR levels have previously been demonstrated to associate with the risk of developing cancer, cardiovascular disease and type 2 diabetes later in life in the general population [7]. Importantly, these associations were independent of CRP, which is known for its predictive value in cardiovascular disease [7,102].7 Potential roles of suPAR in SLE pathogenesisAssessment of circulating suPAR levels at the clinical laboratory could possibly become a future way to estimate organ damage in SLE, and suPAR would be an even more appealing biomarker candidate if the levels could be mechanistically linked to the disease. The pathogenesis of SLE is notoriously complex and not fully understood, but includes disturbances in t...

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“…The plasminogen activator (PA) system is a general proteolytic enzyme system that has been suggested to play an important role in the degradation of the extracellular matrix (ECM) during the development of RA (14,15). Plasmin, the key component of the PA system, is generated by conversion of the precursor plasminogen by 2 distinct physiologic PAs, tissue PA (tPA) and urokinase PA (uPA) (16).…”

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confidence: 99%

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

Guo

Holmdahl

et al. 2005

Arthritis & Rheumatism

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Objective. To investigate the contrasting roles of plasminogen deficiency between models of collageninduced arthritis (CIA) and antigen-induced arthritis (AIA).Methods. We developed a new animal model of arthritis, which we have called local injection-induced arthritis (LIA). In this model, we replaced methylated bovine serum albumin, which is normally used as an immunogen and is injected intraarticularly into the knee joint, with type II collagen (CII) to induce AIA. The severity of CIA, LIA, and AIA in wild-type and plasminogen-deficient mice was evaluated by clinical scoring or histologic grading. Necrosis was determined by histology and immunohistochemistry.Results. After CII immunization alone, wild-type mice developed arthritis in most of the paws as well as in the knee joints, whereas plasminogen-deficient mice were totally resistant to the disease. Local knee injections of CII or saline slightly enhanced the severity of the knee arthritis in wild-type mice during a 60-day experimental period. Unexpectedly, the plasminogendeficient mice also developed arthritis in joints that were injected with CII or saline. However, the arthritis was milder than that in their wild-type littermates. Sustained tissue necrosis was found only in the plasminogen-deficient mice after the local injection.Conclusion. Our data show that both the antigen and the joint trauma caused by the local injection are critical to explaining the contrasting roles of plasminogen deficiency in CIA and AIA. This further indicates that CIA and AIA have distinct pathogenic mechanisms. The data also suggest that plasmin may be required for the induction of these arthritis models that are critically dependent on complement activation.

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Plasminogen activators and their inhibitors in synovial fluids from normal, osteoarthritis, and rheumatoid arthritis knees.

Cited by 55 publications

References 27 publications

Interleukin-17F Down-Regulates the Plasminogen/Plasmin Pathway in Chondrocytes

Interleukin-17F Down-Regulates the Plasminogen/Plasmin Pathway in Chondrocytes

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

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