Antisense targeting of the urokinase receptor blocks urokinase-dependent proliferation, chemoinvasion, and chemotaxis of human synovial cells and chondrocytes in vitro.
Proliferation and invasion of synovial pannus in rheumatoid arthritis and cartilage remodeling in osteoarthritis are key events in development of disability of arthritic joints. The mechanisms that trigger these events are still poorly understood. The production of urokinase-type plasminogen activator (u-PA) by synovial cells and chondrocytes and the subsequent interaction of u-PA with its membrane receptor (u-PAR) is under the control of a variety of growth factors and cytokines released within the inflamed joints. Here we show that u-PA, on interaction with the specific receptor, regulates movement and invasion as well as proliferation of human synovial cells and chondrocytes. Targeting the urokinase receptor with an antisense oligonucleotide blocks the u-PA-dependent synoviocyte and chondrocyte proliferation and chemoinvasion, suggesting a possible use for this new class of drugs in the progression of the disease in rheumatoid arthritis and osteoarthritis.
Fibbi
G
G
Institute of General Pathology of Florence University, Firenze, Italy.
Pucci
M
M
Serni
U
U
Cerinic
M M
MM
Del Rosso
M
M
D002358:Cartilage, Articular / Q000166:cytology*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator; D013582:Synovial Fluid / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism / Q000502:physiology
D006131:Growth Inhibitors; D016376:Oligonucleotides, Antisense; C524898:PLAUR protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator