title: The proinflammatory cytokines interleukin-1α and tumor necrosis factor α promote the expression and secretion of proteolytically active cathepsin S from human chondrocytes.
abstract: Osteoarthritis and rheumatoid arthritis are destructive joint diseases that involve the loss of articular cartilage. Degradation of cartilage extracellular matrix is believed to occur due to imbalance between the catabolic and anabolic processes of resident chondrocytes. Previous work has suggested that various lysosomal cysteine cathepsins participate in cartilage degeneration; however, their exact roles in disease development and progression have not been elucidated. In order to study degradation processes under conditions resembling the in vivo milieu of the cartilage, we cultivated chondrocytes on a type II collagen-containing matrix. Stimulation of the cultivated chondrocytes with interleukin-1α and/or tumor necrosis factor α resulted in a time-dependent increase in cathepsin S expression and induced its secretion into the conditioned media. Using a novel bioluminescent activity-based probe, we were able to demonstrate a significant increase in proteolytic activity of cathepsin S in the conditioned media of proinflammatory cytokine-stimulated chondrocytes. For the first time, cathepsin S was demonstrated to be secreted from chondrocytes upon stimulation with the proinflammatory cytokines, and displayed proteolytic activity in culture supernatants. Its stability at neutral pH and potent proteolytic activity on extracellular matrix components mean that cathepsin S may contribute significantly to cartilage degradation and may thus be considered a potential drug target in joint diseases.
authors.affiliation: Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia. dejan.caglic@ijs.si
authors.forename: Dejan
authors.initials: D
authors.lastname: Caglič
authors.forename: Urška
authors.initials: U
authors.lastname: Repnik
authors.forename: Christopher
authors.initials: C
authors.lastname: Jedeszko
authors.forename: Gregor
authors.initials: G
authors.lastname: Kosec
authors.forename: Catherine
authors.initials: C
authors.lastname: Miniejew
authors.forename: Maik
authors.initials: M
authors.lastname: Kindermann
authors.forename: Olga
authors.initials: O
authors.lastname: Vasiljeva
authors.forename: Vito
authors.initials: V
authors.lastname: Turk
authors.forename: K Ulrich
authors.initials: KU
authors.lastname: Wendt
authors.forename: Bonnie F
authors.initials: BF
authors.lastname: Sloane
authors.forename: Mary B
authors.initials: MB
authors.lastname: Goldring
authors.forename: Boris
authors.initials: B
authors.lastname: Turk
mesh_terms: D002403:Cathepsins / Q000096:biosynthesis* / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000378:metabolism*; D059748:Proteolysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D053582:Interleukin-1alpha; D014409:Tumor Necrosis Factor-alpha; D002403:Cathepsins; C028217:cathepsin S