title: Urokinase-type plasminogen activator and arthritis progression: role in systemic disease with immune complex involvement.
abstract: BACKGROUND
  Urokinase-type plasminogen activator (u-PA) has been implicated in fibrinolysis, cell migration, latent cytokine activation, cell activation, T-cell activation, and tissue remodeling, all of which are involved in the development of rheumatoid arthritis. Previously, u-PA has been reported to play a protective role in monoarticular arthritis models involving mBSA as the antigen, but a deleterious role in the systemic polyarticular collagen-induced arthritis (CIA) model. The aim of the current study is to determine how u-PA might be acting in systemic arthritis models.
  
  
  METHODS
  The CIA model and bone marrow chimeras were used to determine the cellular source of u-PA required for the arthritis development. Gene expression of inflammatory and destructive mediators was measured in joint tissue by quantitiative PCR and protein levels by ELISA. The requirement for u-PA in the type II collagen mAb-induced arthritis (CAIA) and K/BxN serum transfer arthritis models was determined using u-PA(-/-) mice. Neutrophilia was induced in the peritoneal cavity using either ovalbumin/anti-ovalbumin or the complement component C5a.
  
  
  RESULTS
  u-PA from a bone marrow-derived cell was required for the full development of CIA. The disease in u-PA(-/-) mice reconstituted with bone marrow from C57BL/6 mice was indistinguishable from that in C57BL/6 mice, in terms of clinical score, histologic features, and protein and gene expression of key mediators. u-PA(-/-) mice were resistant to both CAIA and K/BxN serum transfer arthritis development. u-PA(-/-) mice developed a reduced neutrophilia and chemokine production in the peritoneal cavity following ovalbumin/anti-ovalbumin injection; in contrast, the peritoneal neutrophilia in response to C5a was u-PA independent.
  
  
  CONCLUSIONS
  u-PA is required for the full development of systemic arthritis models involving immune complex formation and deposition. The cellular source of u-PA required for CIA is bone marrow derived and likely to be of myeloid origin. For immune complex-mediated peritonitis, and perhaps some other inflammatory responses, it is suggested that the u-PA involvement may be upstream of C5a signaling.
authors.affiliation: Arthritis and Inflammation Research Centre, Department of Medicine, The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia. adcook@unimelb.edu.au
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cook
authors.forename: Christine M
authors.initials: CM
authors.lastname: De Nardo
authors.forename: Emma L
authors.initials: EL
authors.lastname: Braine
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Turner
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
authors.forename: Kerrie J
authors.initials: KJ
authors.lastname: Way
authors.forename: S Kaye
authors.initials: SK
authors.lastname: Beckman
authors.forename: Jason C
authors.initials: JC
authors.lastname: Lenzo
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006614:Hindlimb; D007105:Immune Complex Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D007596:Joints / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D010047:Ovalbumin / Q000494:pharmacology; D010538:Peritonitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000235:genetics*
chemical_list: D016207:Cytokines; D010047:Ovalbumin; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9