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

Abstract

Key Points Deficiency in uPA or uPAR renders DBA/1 mice less susceptible to CIA. Expression of uPAR in bone marrow–derived cells promotes arthritis pathogenesis.

Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models

“…Experimental arthritis in the systemic CIA model is virtually eliminated in uPA-deficient mice that are backcrossed to the CIAsusceptible DBA/1 strain (11). The disease-promoting effect of uPA was also seen in earlier CIA studies using other mouse strains (7,9,10), as well as in the type II collagen Ab-induced arthritis and K/BxN Ab transfer models (10).…”

“…A key physiological role of uPA is the activation, by limited proteolysis, of the plasmaborne zymogen plasminogen to plasmin, which, in turn, is the central fibrinolytic protease. In some arthritis models, uPA gene deficiency precludes disease formation (10,11), although studies suggest a paradoxical situation in which uPA can promote or inhibit the progression of arthritis, depending on the animal model (7,(9)(10)(11)(16)(17)(18). A similar model-specific or even joint-specific duality has been shown in plasminogen-deficient mice (7,8,16,19).…”

“…Analyses of key coagulation factors in animal models of arthritis identify disease-promoting roles for tissue factor (3), thrombin (4,5), and fibrinogen (6). Surprisingly, similar analyses of key fibrinolytic proteins also identify arthritis-promoting effects of plasminogen (7,8), urokinase-type plasminogen activator (uPA) (7,(9)(10)(11), and the uPA receptor (uPAR) (11,12). Expression of fibrinolytic factors, such as uPA and its cognate inhibitor (plasminogen activator inhibitor type 1) and receptor (uPAR), has been documented in joint tissue from patients with RA (13)(14)(15), but the cellular origin of these factors remains unclear.…”

“…uPA is also involved in the inflammatory process via a complex effect on macrophage motility, in which it plays a nonproteolytic role in adhesion and migration, whereas its proteolytic activity is required for efficient macrophage invasion through matrix barriers (24). It is not clear whether the proteolytic capacity of uPA or the binding of uPA to uPAR is critical for promoting arthritic inflammation in vivo, but the strong proinflammatory effects identified for uPA, uPAR, and plasminogen in the collagen-induced arthritis (CIA) model (7,11) suggest that tethering of uPA proteolytic capacity on the cell surface plays a role. However, there are no reports in arthritis models of Ab-based inhibition of uPA or uPAR functions and, in fact, no therapeutic studies at all that directly target the proteolytic capacity of uPA in arthritis models.…”

Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia

“…Findings indicate a fundamental role for urokinase plasminogen activator (uPA) and uPA receptor-expressing hematopoietic cells in driving arthritis incidence and progression in autoimmune-driven arthritis (left panel). 15,16 Additionally, plasminogen appears to be a key molecular determinant of tumor necrosis factor α-driven inflammatory joint disease capable of driving or ameliorating arthritis pathogenesis in distinct anatomic locations in the same subject (right panel). 17 Spatiotemporal regulation of plasminogen activation and its disruption Tetsumei Urano MD, PhD 1 1 Hamamatsu University School of Medicine, Hamamatsu, Japan Email: uranot@hama-med.ac.jp C-terminal lysine in partially digested fibrin is a key factor in spatiotemporal regulation of fibrinolysis.…”