title: Monosodium Urate and Tumor Necrosis Factor-α Increase Apoptosis in Human Chondrocyte Cultures.
abstract: Monosodium urate and tumor necrosis factor-α, are two potent mediators of separate inflammatory response pathways in arthritic joints where inflammation may be accompanied by the loss of chondrocyte vitality via apoptosis. To address this possibilityin vitro, chondrocyte cultures were employed to determine the extent to which monosodium urate and recombinant TNF-α altered the frequency of apoptotic chondrocytes. Apoptosis as a function of the activation of p38 kinase, C-Jun-terminal kinase, signal transducer and activator of transcription-3 and/or the activity of xanthine oxidase was also studied. Using normal human chondrocytes, monosodium urate or recombinant tumor necrosis factor-α increased the frequency of apoptosis and activity of xanthine oxidase. However, the xanthine oxidase-specific inhibitor, febuxostat, failed to blunt this response. Monosodium urate, tumor necrosis factor-α or the Janus kinase inhibitor, AG-490, increased the frequency of apoptotic nuclei in macroaggregate pellet cultures initiated from juvenile human chondrocytes, but not in pellet cultures derived from mesenchymal stem cells. In OA chondrocytes, activation of p38, C-Jun-NH2-kinase and signal transducer and activator of transcription-3 preceded apoptosis. Activation of signal transducer and activator of transcription-3 also was seen in pellet cultures initiated from juvenile chondrocytes and MSCs incubated with MSU, recombinant tumor necrosis factor-α or febuxostat, but apoptosis was increased only in the pellet cultures derived from juvenile chondrocytes. Although AG-490 or the combination of AG-490 and febuxostat inhibited signal transducer and activator of transcription-3 activation, apoptosis was unaffected. These results showed that recombinant tumor necrosis factor-α, monosodium urate and AG-490 increased apoptosis in normal human chondrocytes, OA chondrocytes and human juvenile chondrocyte pellet cultures, but not in chondrocyte pellet cultures initiated from MSCs. The increased frequency of apoptotic chondrocytes in response to recombinant tumor necrosis factor-α or monosodium urate was not dependent on either activation of STAT3 or the activity of XO.
authors.affiliation: Department of Medicine/Division of Rheumatic Diseases, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA 44106-5076 ; Department of Anatomy, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA 44106-5076.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Malemud
authors.affiliation: Department of Ophthalmology and the Visual Sciences Research Center, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA 44106.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology and the Visual Sciences Research Center, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA 44106.
authors.forename: Eric
authors.initials: E
authors.lastname: Pearlman
authors.affiliation: Department of Orthopaedics, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA 44106.
authors.forename: Nell M
authors.initials: NM
authors.lastname: Ginley
authors.affiliation: Department of Orthopaedics, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA 44106.
authors.forename: Amad
authors.initials: A
authors.lastname: Awadallah
authors.affiliation: Department of Medicine/Division of Rheumatic Diseases, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA 44106-5076.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Wisler
authors.affiliation: Department of Orthopaedics, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA 44106 ; Benaroya Research Institute at Virginia Mason, Seattle, WA, USA 98101-2795.
authors.forename: James E
authors.initials: JE
authors.lastname: Dennis
keywords: Apoptosis; Arthritis; Chondrocytes; Human; Monosodium urate; Tumor Necrosis Factor-α (TNF-α)