The
plasminogen activation (PA) system has been implicated in driving inflammatory
arthritis, but the precise contribution of PA system components to
arthritis pathogenesis remains poorly defined. Here, the role of
urokinase plasminogen activator (uPA) and its cognate
receptor (uPAR) in the development and severity of inflammatory
joint disease was determined using uPA- and uPAR-deficient mice inbred to the strain DBA/1J, a genetic background highly susceptible to
collagen-induced arthritis (CIA). Mice deficient in uPA displayed a near-complete amelioration of macroscopic and histological inflammatory
joint disease following CIA challenge. Similarly, CIA-challenged uPAR-deficient mice exhibited significant amelioration of
arthritis incidence and severity. Reduced disease development in uPA-deficient and uPAR-deficient mice was not due to an altered adaptive immune response to the CIA challenge. Reciprocal bone marrow transplant studies indicated that uPAR-driven CIA was due to expression by hematopoietic-derived cells, as mice with uPAR-deficient bone marrow challenged with CIA developed significantly reduced macroscopic and histological
joint disease as compared with mice with uPAR expression limited to non-hematopoietic-derived cells. These findings indicate a fundamental role for uPAR-expressing hematopoietic cells in driving
arthritis incidence and progression. Thus, uPA/uPAR-mediated cell surface proteolysis and/or uPAR-mediated signaling events promote inflammatory
joint disease, indicating that disruption of this key proteolytic/signaling system may provide a novel therapeutic strategy to limit clinical
arthritis.