Carprofen inhibits the release of matrix metalloproteinases 1, 3, and 13 in the secretome of an explant model of articular ... View Full Text


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Article Info

DATE

2013-12-30

AUTHORS

Adam Williams, Julia R Smith, David Allaway, Pat Harris, Susan Liddell, Ali Mobasheri

ABSTRACT

INTRODUCTION: Arthritic diseases are characterized by the degradation of collagenous and noncollagenous extracellular matrix (ECM) components in articular cartilage. The increased expression and activity of matrix metalloproteinases (MMPs) is partly responsible for cartilage degradation. This study used proteomics to identify inflammatory proteins and catabolic enzymes released in a serum-free explant model of articular cartilage stimulated with the pro-inflammatory cytokine interleukin 1β (IL-1β). Western blotting was used to quantify the release of selected proteins in the presence or absence of the cyclooxygenase-2 specific nonsteroidal pro-inflammatory drug carprofen. METHODS: Cartilage explant cultures were established by using metacarpophalangeal joints from horses euthanized for purposes other than research. Samples were treated as follows: no treatment (control), IL-1β (10 ng/ml), carprofen (100 μg/ml), and carprofen (100 μg/ml) + IL-1β (10 ng/ml). Explants were incubated (37°C, 5% CO2) over twelve day time courses. High-throughput nano liquid chromatography/mass spectrometry/mass spectrometry uncovered candidate proteins for quantitative western blot analysis. Proteoglycan loss was assessed by using the dimethylmethylene blue (DMMB) assay, which measures the release of sulfated glycosaminoglycans (GAGs). RESULTS: Mass spectrometry identified MMP-1, -3, -13, and the ECM constituents thrombospondin-1 (TSP-1) and fibronectin-1 (FN1). IL-1β stimulation increased the release of all three MMPs. IL-1β also stimulated the fragmentation of FN1 and increased chondrocyte cell death (as assessed by β-actin release). Addition of carprofen significantly decreased MMP release and the appearance of a 60 kDa fragment of FN1 without causing any detectable cytotoxicity to chondrocytes. DMMB assays suggested that carprofen initially inhibited IL-1β-induced GAG release, but this effect was transient. Overall, during the two time courses, GAG release was 58.67% ± 10.91% (SD) for IL-1β versus 52.91% ± 9.35% (SD) with carprofen + IL-1β. CONCLUSIONS: Carprofen exhibits beneficial anti-inflammatory and anti-catabolic effects in vitro without causing any detectable cytotoxicity. Combining proteomics with this explant model provides a sensitive screening system for anti-inflammatory compounds. More... »

PAGES

r223-r223

References to SciGraph publications

  • 2013-01-08. MMP13 is a critical target gene during the progression of osteoarthritis in ARTHRITIS RESEARCH & THERAPY
  • 2000-12. Osteoarthritis and cartilage: The role of cytokines in CURRENT RHEUMATOLOGY REPORTS
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/ar4424

    DOI

    http://dx.doi.org/10.1186/ar4424

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1017100244

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/24373218


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