title: S100A8/A9, a potent serum and molecular imaging biomarker for synovial inflammation and joint destruction in seronegative experimental arthritis.
abstract: Seronegative joint diseases are characterized by a lack of well-defined biomarkers since autoantibodies are not elevated. Calprotectin (S100A8/A9) is a damage-associated molecular pattern (DAMP) which is released by activated phagocytes, and high levels are found in seronegative arthritides. In this study, we investigated the biomarker potential of systemic and local levels of these S100 proteins to assess joint inflammation and joint destruction in an experimental model for seronegative arthritis.
  
  
  
  Serum levels of S100A8/A9 and various cytokines were monitored during disease development in interleukin-1 receptor antagonist (IL-1Ra)-/-mice using ELISA and multiplex bead-based immunoassay, and were correlated to macroscopic and microscopic parameters for joint inflammation, bone erosion, and cartilage damage. Local expression of S100A8 and S100A9 and matrix metalloproteinase (MMP)-mediated cartilage damage in the ankle joints were investigated by immunohistochemistry. In addition, local S100A8 and activated MMPs were monitored in vivo by optical imaging using anti-S100A8-Cy7 and AF489-Cy5.5, a specific tracer for activated MMPs.
  
  
  
  Serum levels of S100A8/A9 were significantly increased in IL-1Ra-/-mice and correlated with macroscopic joint swelling and histological inflammation, while serum levels of pro-inflammatory cytokines did not correlate with joint swelling. In addition, early serum S100A8/A9 levels were prognostic for disease outcome at a later stage. The increased serum S100A8/A9 levels were reflected by an increased expression of S100A8 and S100A9 within the ankle joint, as visualized by molecular imaging. Next to inflammatory processes, serum S100A8/A9 also correlated with histological parameters for bone erosion and cartilage damage. In addition, arthritic IL-1Ra-/-mice with increased synovial S100A8 and S100A9 expression showed increased cartilage damage that coincided with MMP-mediated neoepitope expression and in vivo imaging of activated MMPs.
  
  
  
  Expression of S100A8 and S100A9 in IL-1Ra-/-mice strongly correlates with synovial inflammation, bone erosion, and cartilage damage, underlining the potential of S100A8/A9 as a systemic and local biomarker in seronegative arthritis not only for assessing inflammation but also for assessing severity of inflammatory joint destruction.
authors: Experimental Rheumatology, Radboud University Medical Center, PO Box 9101, 6525, GA, Nijmegen, The Netherlands.
authors: Edwin J W
authors: EJ
authors: Geven
authors: Experimental Rheumatology, Radboud University Medical Center, PO Box 9101, 6525, GA, Nijmegen, The Netherlands.
authors: Martijn H J
authors: MH
authors: van den Bosch
authors: Experimental Rheumatology, Radboud University Medical Center, PO Box 9101, 6525, GA, Nijmegen, The Netherlands.
authors: Irene
authors: I
authors: Di Ceglie
authors: Experimental Rheumatology, Radboud University Medical Center, PO Box 9101, 6525, GA, Nijmegen, The Netherlands.
authors: Giuliana
authors: G
authors: Ascone
authors: Experimental Rheumatology, Radboud University Medical Center, PO Box 9101, 6525, GA, Nijmegen, The Netherlands.
authors: Shahla
authors: S
authors: Abdollahi-Roodsaz
authors: Experimental Rheumatology, Radboud University Medical Center, PO Box 9101, 6525, GA, Nijmegen, The Netherlands.
authors: Annet W
authors: AW
authors: Sloetjes
authors: European Institute for Molecular Imaging, University of Münster, Münster, Germany.
authors: Sven
authors: S
authors: Hermann
authors: European Institute for Molecular Imaging, University of Münster, Münster, Germany.
authors: Michael
authors: M
authors: Schäfers
authors: Experimental Rheumatology, Radboud University Medical Center, PO Box 9101, 6525, GA, Nijmegen, The Netherlands.
authors: Fons A J
authors: FA
authors: van de Loo
authors: Experimental Rheumatology, Radboud University Medical Center, PO Box 9101, 6525, GA, Nijmegen, The Netherlands.
authors: Peter M
authors: PM
authors: van der Kraan
authors: Experimental Rheumatology, Radboud University Medical Center, PO Box 9101, 6525, GA, Nijmegen, The Netherlands.
authors: Marije I
authors: MI
authors: Koenders
authors: Department of Pediatric Rheumatology and Immunology, University of Münster, Münster, Germany.
authors: Dirk
authors: D
authors: Foell
authors: Institute of Immunology, University of Münster, Münster, Germany.
authors: Johannes
authors: J
authors: Roth
authors: Institute of Immunology, University of Münster, Münster, Germany.
authors: Thomas
authors: T
authors: Vogl
authors: Experimental Rheumatology, Radboud University Medical Center, PO Box 9101, 6525, GA, Nijmegen, The Netherlands. Peter.vanLent@radboudumc.nl.
authors: Peter L E M
authors: PL
authors: van Lent
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology*; D015415:Biomarkers / Q000032:analysis*; D040501:Calgranulin A / Q000032:analysis / Q000096:biosynthesis*; D040502:Calgranulin B / Q000032:analysis / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout
chemical_list: D015415:Biomarkers; D040501:Calgranulin A; D040502:Calgranulin B
keywords: Biomarker; Cartilage damage; IL-1Ra; Imaging; Inflammation; MMP; S100A8/A9; Seronegative arthritis