Interleukin-1beta-induced expression of the urokinase-type plasminogen activator receptor and its co-localization with MMPs in human articular chondrocytes.
The urokinase-type plasminogen activator receptor (uPAR) plays a critical role in cartilage degradation during osteoarthritis as it regulates pericellular proteolysis mediated by serine proteinases. Another important family of proteinases responsible for ECM destruction in arthritis are the matrix metalloproteinases (MMPs). MMPs are regulated by IL-1beta, a cytokine that plays a pivotal role in pathogenesis of osteoarthritis. This study was undertaken to address two questions: 1. Is uPAR-expression regulated by proinflammatory cytokines such as IL-1beta? 2. Does a functional co-localization exist between uPAR and MMPs? By immunohistochemical analysis we observed enhanced expression of uPAR on chondrocytes derived from osteoarthritic human cartilage compared to non-osteoarthritic controls. We found an IL-1beta-mediated expression of uPAR by immunoelectron microscopy. Western blot analysis demonstrated that IL-1beta-stimulated expression of uPAR on chondrocytes in vitro increased in a dose-dependent manner. Furthermore, we found a functional co-localization between uPAR and MMP-9 on IL-1beta-stimulated chondrocytes by means of a co-immunoprecipitation assay. Expression of uPAR in osteoarthritic cartilage but not in healthy cartilage suggests that uPAR plays a role in cartilage breakdown. We propose that uPAR-mediated effects e.g. pericellular proteolysis are one of other cytokine (IL-1beta)-mediated events that contribute to the pathogenesis of osteoarthritis. Furthermore, we found that MMPs and uPAR were part of the same cell surface complexes in chondrocytes. This finding underlines a functional interaction between MMPs and the serine proteinase system in the fine regulation of pericellular proteolysis. Interfering with uPAR signaling may present a novel target in arthritis therapy to prevent excessive proteolytic degradation.
Schwab
W
W
Institute of Anatomy, Technical University Dresden, Germany.
Schulze-Tanzil
G
G
Mobasheri
A
A
Dressler
J
J
Kotzsch
M
M
Shakibaei
M
M
D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000378:metabolism*; D016253:Microscopy, Immunoelectron; D011233:Precipitin Tests; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000648:ultrastructure; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism / Q000648:ultrastructure
D000911:Antibodies, Monoclonal; D007375:Interleukin-1; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases