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Myeloid related proteins S100A8/S100A9 regulate joint inflammation and cartilage destruction during antigen-induced arthritis
  1. P LEM van Lent (p.vanlent{at}reuma.umcn.nl)
  1. Radboud University Medical Centre Nijmegen, Netherlands
    1. L Grevers
    1. Radboud University Medicial Centre Nijmegen, Netherlands
      1. A B Blom
      1. Radboud University Medical Centre Nijmegen, Netherlands
        1. A Sloetjes
        1. Radboud University Medical Centre Nijmegen, Netherlands
          1. J SY Mort
          1. Shriners Hospital for Children and department of Surgery, Montreal, Quebec, Canada
            1. T Vogl
            1. University of Munster, Germany
              1. W Nacken
              1. University of Munster, Germany
                1. W B van den Berg
                1. Radboud University Medical Centre Nijmegen, Netherlands
                  1. J Roth
                  1. University of Munster, Germany

                    Abstract

                    Objective: To study the active involvement of S100A8 and A9 in joint inflammation and cartilage destruction during antigen-induced arthritis (AIA).

                    Methods: Joint inflammation and cartilage destruction was measured with 99mTc uptake and histology. The role of S100A8/A9 was investigated by inducing AIA in S100A9-/- mice, which lacks also S100A8 at protein level, or after intra-articular injection of rS100A8 in mouse kneejoints. Cartilage destruction was measured using immunolocalisation of the neoepitope VDIPEN or NITEGE. mRNA levels of MMPs and cytokines were measured using RT-PCR.

                    Results: Immunization of S100A9-/- mice with the antigen mBSA induced normal cellular and humoral responses, not different from WT controls. However, joint swelling measured at day 3 and 7 after AIA induction was significantly lower (36 and 70% respectively). Histologically, at day 7 AIA, cellular mass was much lower (63- 80%) and proteoglycan depletion from cartilage layers was significantly reduced (between 50-95%). Cartilage destruction mediated by MMPs was absent in S100A9-/- mice but clearly present in controls. MMP3, 9 and 13 mRNA levels were significantly lowered in arthritic synovia of S100A9-/-. In vitro stimulation of macrophages by the heterodimer S100A8/A9 or S100A8 elevated mRNA levels of MMP3, 9 and in particular MMP13. Intra-articular injection of S100A8 caused prominent joint inflammation and depletion of proteoglycans at day 1. Significant upregulation of mRNA levels of S100A8/A9, cytokines (IL-1), MMPs (MMP-3, MMP-13 and ADAMTS4) was found in the synovium and correlated with strong upregulation of NITEGE neoepitopes within the cartilage layers.

                    Conclusions: S100A8/A9 regulate joint inflammation and cartilage destruction during antigen-induced arthritis.

                    • S100A8/S100A9
                    • calprotectin
                    • cartilage destruction
                    • experimental arthritis
                    • synovial lining macrophages

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