title: Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis.
abstract: Plasmin is essential for metalloproteases activation, endothelial cell migration and degradation of the extracellular matrix. The process is common to neoangiogenesis pannus formation and cartilage degradation within arthritic joints. Since 80% of synovial cells express urokinase plasminogen activator receptor (uPAR), we investigated the inhibition of plasmin activation in a collagen-induced arthritis (CIA) mice model, by expressing a uPA/uPAR antagonist molecule (ATF) fused to human serum albumin (HSA) to extend its serum half-life. Overexpression was obtained with an adenoviral vector expressing the chimeric murine ATF-HSA. We showed that the genetic coupling did not significantly reduce the ability of the ATF moiety to interact with its receptor uPAR. The chimeric protein was detectable in the sera of injected mice 7 days following Ad-mATF-HSA injection, then decreased in parallel with the anti-HSA titer increase. Systemic Ad-mATF-HSA injection performed on day 25 following CIA induction decreased the incidence of arthritis and the severity of the disease. Moreover, synovial angiogenesis in arthritic paws was decreased after Ad-mATF-HSA gene transfer, as assessed by smooth muscle actin immunostaining. The preventive effect observed on arthritis was related to the decrease in angiogenesis, rather than inhibition of extracellular matrix degradation.
authors.affiliation: INSERM U475, Montpellier, France.
authors.forename: F
authors.initials: F
authors.lastname: Apparailly
authors.forename: C
authors.initials: C
authors.lastname: Bouquet
authors.forename: V
authors.initials: V
authors.lastname: Millet
authors.forename: D
authors.initials: D
authors.lastname: Noel
authors.forename: C
authors.initials: C
authors.lastname: Jacquet
authors.forename: P
authors.initials: P
authors.lastname: Opolon
authors.forename: M
authors.initials: M
authors.lastname: Perricaudet
authors.forename: J
authors.initials: J
authors.lastname: Sany
authors.forename: P
authors.initials: P
authors.lastname: Yeh
authors.forename: C
authors.initials: C
authors.lastname: Jorgensen
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000906:Antibodies / Q000097:blood; D001169:Arthritis, Experimental / Q000473:pathology / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009389:Neovascularization, Pathologic; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012709:Serum Albumin / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000906:Antibodies; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D014568:Urokinase-Type Plasminogen Activator