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The plasminogen activation system in inflammatory arthritis pathogenesis
Author(s) -
Flick Matthew
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.241.2
Subject(s) - pathogenesis , arthritis , medicine , rheumatoid arthritis , immunology , inflammation , synovitis , polyarthritis , urokinase receptor , plasminogen activator , pathology
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. Our laboratory has evaluated both plasminogen activators and plasminogen itself to define the role of the PA system in inflammatory joint disease. First, we examined the influence of plasminogen deficiency on TNFα‐driven arthritis in Tg197 mice that spontaneously develop early‐onset joint disease that progresses to debilitating polyarthritis. Comparative clinical analyses of both the distal joints of the fore‐ and hind‐paws and proximal joints of the knees revealed that plasminogen deficiency resulted in significantly elevated arthritic disease in distal joints but decreased arthritic disease within larger proximal joints relative to control animals. Thus, plasminogen appears to be a key molecular determinant of inflammatory joint disease capable of simultaneously driving or ameliorating arthritis pathogenesis in distinct anatomic locations in the same subject. 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. Further, inflammatory joint disease in CIA‐challenged mice was dependent on the expression of uPAR by hematopoietic‐derived cells as determined by reciprocal bone marrow transplant studies. 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.