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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.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>To 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<jats:sup>-\/-<\/jats:sup> mice. This modified model and the antigen-induced arthritis (AIA) model were also used in u-PA<jats:sup>-\/-<\/jats:sup> 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.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>In our modified arthritis model, u-PA<jats:sup>-\/-<\/jats:sup> 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<jats:sup>-\/-<\/jats:sup> 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-1\u03b2), aggrecanases (ADAMTS-4 and -5) and MMPs (MMP3 and MMP13) were all sustained over time following AIA induction in u-PA<jats:sup>-\/-<\/jats:sup> mice compared with C57BL\/6 mice.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>We 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<jats:sup>-\/-<\/jats:sup> mice with monoarticular arthritis, it is unlikely that u-PA\/plasmin-mediated proteolysis is contributing directly to this tissue destruction\/remodeling.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/ar3171","type":"journal-article","created":{"date-parts":[[2010,11,11]],"date-time":"2010-11-11T19:15:39Z","timestamp":1289502939000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Urokinase-type plasminogen activator and arthritis progression: contrasting roles in systemic and monoarticular arthritis models"],"prefix":"10.1186","volume":"12","author":[{"given":"Christine M","family":"De Nardo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason C","family":"Lenzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarrad","family":"Pobjoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A","family":"Hamilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D","family":"Cook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2010,10,25]]},"reference":[{"key":"3027_CR1","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1007\/PL00000615","volume":"56","author":"JP Irigoyen","year":"1999","unstructured":"Irigoyen JP, Munoz-Canoves P, Montero L, Koziczak M, Nagamine Y: The plasminogen activator system: biology and regulation. 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