Urokinase-type plasminogen activator and arthritis progression: contrasting roles in systemic and monoarticular arthritis models

Abstract

IntroductionUrokinase-type plasminogen activator (u-PA) has been implicated in tissue destruction/remodeling. The absence of u-PA results in resistance of mice to systemic immune complex-driven arthritis models; monoarticular arthritis models involving an intra-articular (i.a.) antigen injection, on the other hand, develop more severe arthritis in its absence. The aims of the current study are to investigate further these contrasting roles that u-PA can play in the pathogenesis of inflammatory arthritis and to determine whether u-PA is required for the cartilage and bone destruction associated with disease progression.MethodsTo determine how the different pathogenic mechanisms leading to arthritis development in the different models may explain the contrasting requirement for u-PA, the systemic, polyarticular, immune complex-driven K/BxN arthritis model was modified to include an i.a. injection of saline as a local trauma in u-PA-/- mice. This modified model and the antigen-induced arthritis (AIA) model were also used in u-PA-/- mice to determine the requirement for u-PA in joint destruction. Disease severity was determined by clinical and histologic scoring. Fibrin(ogen) staining and the matrix metalloproteinase (MMP)-generated neoepitope DIPEN staining were performed by immunohistochemistry. Gene expression of inflammatory and destructive mediators was measured in joint tissue by quantitative PCR.ResultsIn our modified arthritis model, u-PA-/- mice went from being resistant to arthritis development following K/BxN serum transfer to being susceptible following the addition of an i.a. injection of saline. u-PA-/- mice also developed more sustained AIA compared with C57BL/6 mice, including reduced proteoglycan levels and increased bone erosions, fibrin(ogen) deposition and DIPEN expression. Synovial gene expression of the proinflammatory mediators (TNF and IL-1β), aggrecanases (ADAMTS-4 and -5) and MMPs (MMP3 and MMP13) were all sustained over time following AIA induction in u-PA-/- mice compared with C57BL/6 mice.ConclusionsWe propose that u-PA has a protective role in arthritis models with 'wound healing-like' processes following local trauma, possibly through u-PA/plasmin-mediated fibrinolysis, but a deleterious role in systemic models that are critically dependent on immune complex formation and complement activation. Given that cartilage proteoglycan loss and bone erosions were present and sustained in u-PA-/- mice with monoarticular arthritis, it is unlikely that u-PA/plasmin-mediated proteolysis is contributing directly to this tissue destruction/remodeling.

Urokinase plasminogen activator and receptor promote collagen-induced arthritis through expression in hematopoietic cells

“…In contrast, in the model of antigen-induced arthritis, uPA-deficient mice exhibited increased disease pathology. 8,13 The basis for this distinct phenotype was linked to the wound field generated by the intra-articular injection. In immune complex-driven arthritis, where uPA deficiency ameliorates disease, the elimination of uPA results in increased disease if a joint is simultaneously subjected to an intraarticular injection of saline.…”

“…In immune complex-driven arthritis, where uPA deficiency ameliorates disease, the elimination of uPA results in increased disease if a joint is simultaneously subjected to an intraarticular injection of saline. 8 It was proposed that the local wound field resulted in exuberant fibrin deposition, due to loss of uPA/ plasmin-mediated fibrinolysis that in turn promoted local inflammation driving arthritis severity. Thus, in the absence of a local secondary insult, the role of uPA is as a disease driver rather than a protective factor in models of systemic arthritis.…”

“…[1][2][3][4][5] Components of the plasminogen activation (PA) system appear to be particularly powerful determinants of inflammatory arthritis. [6][7][8][9] High levels of urokinase plasminogen activator (uPA) and tissue-type plasminogen activator activity have been documented in synovial tissue from RA patients. 10 Similarly, increased levels of the physiological inhibitors of the PA system, plasminogen activator inhibitors 1 and 2, have been documented in RA tissue.…”

Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain

“…Mice were immunised (day 0) with methylated bovine serum albumin (mBSA; Sigma-Aldrich, St Louis, Missouri, USA), emulsified in CFA, intradermally in the base of the tail 20. Arthritis was induced 7 days later by an intra-articular injection of mBSA into the right knee, the left knee being injected with phosphate-buffered saline (PBS).…”

“…At termination, the knee joints were removed, fixed, decalcified and paraffin embedded 9 14 20. Frontal sections (5 μm) were stained with H&E. For antigen-induced arthritis (AIA), infiltration of cells, cartilage damage and bone erosions were scored separately from 0 (normal) to 3 (severe) 20.…”