Plasminogen Is a Joint‐Specific Positive or Negative Determinant of Arthritis Pathogenesis in Mice

Abstract

Objective A fundamental metric in the diagnosis of arthropathies is the pattern of joint involvement, including differences in proximal versus distal joints and patterns of symmetric or asymmetric disease. The basis for joint selectivity among arthritides and/or within a defined disease such as rheumatoid arthritis remains enigmatic. Coagulation and fibrinolytic activity are observed in both experimental animals with inflammatory joint disease and patients with inflammatory arthritis. However, the contribution of specific hemostatic factors to joint disease is not fully defined. We sought to determine the contribution of the fibrinolytic protease, plasminogen, to tumor necrosis factor α (TNFα)–driven arthritis in distinct joints in mice. Methods The impact of plasminogen and/or fibrinogen genetic deficiencies on arthritis progression was evaluated in Tg197 mice genetically predisposed to spontaneous, nonabating, and erosive polyarthritis due to exuberant human TNFα expression. Results Elimination of plasminogen in Tg197 mice significantly exacerbated the incidence and severity of arthritis within the paw joints, but simultaneously and dramatically diminished the entire spectrum of pathologies within the knee joints of the same animals. These opposing outcomes were both mechanistically linked to fibrin(ogen), in that superimposing fibrinogen deficiency reversed both the proarthritic phenotype in the paws and arthritis resistance in the knees of plasminogen-deficient mice. Intriguingly, the change in disease severity in the knees, but not the paws, was associated with a plasminogen-dependent reduction in matrix metalloproteinase 9 activity. Conclusion Plasminogen is a key molecular determinant of inflammatory joint disease capable of simultaneously driving or ameliorating arthritis pathogenesis in distinct anatomic locations in the same subject.

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

“…Analyses of hemostatic factors in RA disease models have indicated roles for fibrinogen, thrombin, plasminogen, and the plasminogen activators in promoting inflammatory arthritic disease. [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.…”

“…Four-micrometer sections of paraffin-embedded tissue were placed on Colorfrost Plus slides (Fisher Scientific) and processed for hematoxylin and eosin or fibrin(ogen) immunohistochemistry with a rabbit anti-mouse fibrinogen antisera as described previously. 2 A semiquantitative histopathology analysis was performed for each knee joint based on the following scoring criteria for CIA: inflammation (0-3), synovial hyperplasia (0-3), edema (0-3), pannus (0-1), and bone/cartilage loss (0-3) for a total histopathology index (0-26) for knees of a given animal. 1 The Cincinnati Children's Hospital Medical Center Institutional Animal Care and Use Committee approved all experiments performed on mice.…”

Head-to-Head Comparison of Protocol Modifications for the Generation of Collagen-Induced Arthritis in a Specific-Pathogen Free Facility Using DBA/1 Mice

“…Knees were immediately placed in formalin for a minimum of 72 h, decalcified in EDTA, paraffin embedded, and processed in the usual manner for hematoxylin and eosin (H&E) staining (27). Histological slides from the center of the knee joint were scored in a blinded fashion using a histopathologic scoring system as previously published (27). In brief, the scoring system has 5 categories: inflammation (score 03), synovial hyperplasia (score 03), pannus (score 01), edema (score 03), and bone/cartilage loss (score 03).…”

Advances and challenges in hemophilic arthropathy

“…This is further underlined by the fact that opposing effects of plasmin modulation were observed in a model of rheumatoid arthritis in the plasminogen-deficient mouse and depended on the type of joint. 100 In this model mice developed severe arthritis in the distal joints despite decreased MMP activity, whereas proximal joints were protected. 100 The extent to which fibrinolysis dysregulation comprising fibrin depositions, hyperfibrinolysis or reduced fibrinolysis may play a role for HA therefore remains an important open question.…”