title: Alarmin S100A9 Induces Proinflammatory and Catabolic Effects Predominantly in the M1 Macrophages of Human Osteoarthritic Synovium.
abstract: The alarmins S100A8 and S100A9 have been shown to regulate synovial activation, cartilage damage, and osteophyte formation in osteoarthritis (OA). Here we investigated the effect of S100A9 on the production of proinflammatory cytokines and matrix metalloprotease (MMP) in OA synovium, granulocyte macrophage colony-stimulating factor (GM-CSF)-differentiated/macrophage colony-stimulating factor (M-CSF)-differentiated macrophages, and OA fibroblasts.
  
  
  
  We determined which cell types in the synovium produced S100A8 and S100A9. Further, the production of proinflammatory cytokines and MMP, and the activation of canonical Wnt signaling, was determined in human OA synovium, OA fibroblasts, and monocyte-derived macrophages following stimulation with S100A9.
  
  
  
  We observed that S100A8 and S100A9 were mainly produced by GM-CSF-differentiated macrophages present in the synovium, and to a lesser extent by M-CSF-differentiated macrophages, but not by fibroblasts. S100A9 stimulation of OA synovial tissue increased the production of the proinflammatory cytokines interleukin (IL) 1β, IL-6, IL-8, and tumor necrosis factor-α. Additionally, various MMP were upregulated after S100A9 stimulation. Experiments to determine which cell type was responsible for these effects revealed that mainly stimulation of GM-CSF-differentiated macrophages and to a lesser extent M-CSF-differentiated macrophages with S100A9 increased the expression of these proinflammatory cytokines and MMP. In contrast, stimulation of fibroblasts with S100A9 did not affect their expression. Finally, stimulation of GM-CSF-differentiated, but not M-CSF-differentiated macrophages with S100A9 activated canonical Wnt signaling, whereas incubation of OA synovium with the S100A9 inhibitor paquinimod reduced the activation of canonical Wnt signaling.
  
  
  
  Predominantly mediated by M1-like macrophages, the alarmin S100A9 stimulates the production of proinflammatory and catabolic mediators and activates canonical Wnt signaling in OA synovium.
authors.affiliation: From Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Immunology, University of Münster, Münster, Germany.M.H. van den Bosch, MSc, Experimental Rheumatology, Radboud University Medical Center; A.B. Blom, PhD, Experimental Rheumatology, Radboud University Medical Center; R.F. Schelbergen, PhD, Experimental Rheumatology, Radboud University Medical Center; M.I. Koenders, PhD, Experimental Rheumatology, Radboud University Medical Center; F.A. van de Loo, PhD, Experimental Rheumatology, Radboud University Medical Center; W.B. van den Berg, PhD, Professor, Experimental Rheumatology, Radboud University Medical Center; T. Vogl, PhD, Professor, Institute of Immunology, University of Muenster; J. Roth, PhD, Professor, Institute of Immunology, University of Münster; P.M. van der Kraan, PhD, Experimental Rheumatology, Radboud University Medical Center; P.L. van Lent, PhD, Experimental Rheumatology, Radboud University Medical Center.
authors.forename: Martijn H
authors.initials: MH
authors.lastname: van den Bosch
authors.affiliation: From Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Immunology, University of Münster, Münster, Germany.M.H. van den Bosch, MSc, Experimental Rheumatology, Radboud University Medical Center; A.B. Blom, PhD, Experimental Rheumatology, Radboud University Medical Center; R.F. Schelbergen, PhD, Experimental Rheumatology, Radboud University Medical Center; M.I. Koenders, PhD, Experimental Rheumatology, Radboud University Medical Center; F.A. van de Loo, PhD, Experimental Rheumatology, Radboud University Medical Center; W.B. van den Berg, PhD, Professor, Experimental Rheumatology, Radboud University Medical Center; T. Vogl, PhD, Professor, Institute of Immunology, University of Muenster; J. Roth, PhD, Professor, Institute of Immunology, University of Münster; P.M. van der Kraan, PhD, Experimental Rheumatology, Radboud University Medical Center; P.L. van Lent, PhD, Experimental Rheumatology, Radboud University Medical Center.
authors.forename: Arjen B
authors.initials: AB
authors.lastname: Blom
authors.affiliation: From Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Immunology, University of Münster, Münster, Germany.M.H. van den Bosch, MSc, Experimental Rheumatology, Radboud University Medical Center; A.B. Blom, PhD, Experimental Rheumatology, Radboud University Medical Center; R.F. Schelbergen, PhD, Experimental Rheumatology, Radboud University Medical Center; M.I. Koenders, PhD, Experimental Rheumatology, Radboud University Medical Center; F.A. van de Loo, PhD, Experimental Rheumatology, Radboud University Medical Center; W.B. van den Berg, PhD, Professor, Experimental Rheumatology, Radboud University Medical Center; T. Vogl, PhD, Professor, Institute of Immunology, University of Muenster; J. Roth, PhD, Professor, Institute of Immunology, University of Münster; P.M. van der Kraan, PhD, Experimental Rheumatology, Radboud University Medical Center; P.L. van Lent, PhD, Experimental Rheumatology, Radboud University Medical Center.
authors.forename: Rik F
authors.initials: RF
authors.lastname: Schelbergen
authors.affiliation: From Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Immunology, University of Münster, Münster, Germany.M.H. van den Bosch, MSc, Experimental Rheumatology, Radboud University Medical Center; A.B. Blom, PhD, Experimental Rheumatology, Radboud University Medical Center; R.F. Schelbergen, PhD, Experimental Rheumatology, Radboud University Medical Center; M.I. Koenders, PhD, Experimental Rheumatology, Radboud University Medical Center; F.A. van de Loo, PhD, Experimental Rheumatology, Radboud University Medical Center; W.B. van den Berg, PhD, Professor, Experimental Rheumatology, Radboud University Medical Center; T. Vogl, PhD, Professor, Institute of Immunology, University of Muenster; J. Roth, PhD, Professor, Institute of Immunology, University of Münster; P.M. van der Kraan, PhD, Experimental Rheumatology, Radboud University Medical Center; P.L. van Lent, PhD, Experimental Rheumatology, Radboud University Medical Center.
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.affiliation: From Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Immunology, University of Münster, Münster, Germany.M.H. van den Bosch, MSc, Experimental Rheumatology, Radboud University Medical Center; A.B. Blom, PhD, Experimental Rheumatology, Radboud University Medical Center; R.F. Schelbergen, PhD, Experimental Rheumatology, Radboud University Medical Center; M.I. Koenders, PhD, Experimental Rheumatology, Radboud University Medical Center; F.A. van de Loo, PhD, Experimental Rheumatology, Radboud University Medical Center; W.B. van den Berg, PhD, Professor, Experimental Rheumatology, Radboud University Medical Center; T. Vogl, PhD, Professor, Institute of Immunology, University of Muenster; J. Roth, PhD, Professor, Institute of Immunology, University of Münster; P.M. van der Kraan, PhD, Experimental Rheumatology, Radboud University Medical Center; P.L. van Lent, PhD, Experimental Rheumatology, Radboud University Medical Center.
authors.forename: Fons A
authors.initials: FA
authors.lastname: van de Loo
authors.affiliation: From Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Immunology, University of Münster, Münster, Germany.M.H. van den Bosch, MSc, Experimental Rheumatology, Radboud University Medical Center; A.B. Blom, PhD, Experimental Rheumatology, Radboud University Medical Center; R.F. Schelbergen, PhD, Experimental Rheumatology, Radboud University Medical Center; M.I. Koenders, PhD, Experimental Rheumatology, Radboud University Medical Center; F.A. van de Loo, PhD, Experimental Rheumatology, Radboud University Medical Center; W.B. van den Berg, PhD, Professor, Experimental Rheumatology, Radboud University Medical Center; T. Vogl, PhD, Professor, Institute of Immunology, University of Muenster; J. Roth, PhD, Professor, Institute of Immunology, University of Münster; P.M. van der Kraan, PhD, Experimental Rheumatology, Radboud University Medical Center; P.L. van Lent, PhD, Experimental Rheumatology, Radboud University Medical Center.
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.affiliation: From Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Immunology, University of Münster, Münster, Germany.M.H. van den Bosch, MSc, Experimental Rheumatology, Radboud University Medical Center; A.B. Blom, PhD, Experimental Rheumatology, Radboud University Medical Center; R.F. Schelbergen, PhD, Experimental Rheumatology, Radboud University Medical Center; M.I. Koenders, PhD, Experimental Rheumatology, Radboud University Medical Center; F.A. van de Loo, PhD, Experimental Rheumatology, Radboud University Medical Center; W.B. van den Berg, PhD, Professor, Experimental Rheumatology, Radboud University Medical Center; T. Vogl, PhD, Professor, Institute of Immunology, University of Muenster; J. Roth, PhD, Professor, Institute of Immunology, University of Münster; P.M. van der Kraan, PhD, Experimental Rheumatology, Radboud University Medical Center; P.L. van Lent, PhD, Experimental Rheumatology, Radboud University Medical Center.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.affiliation: From Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Immunology, University of Münster, Münster, Germany.M.H. van den Bosch, MSc, Experimental Rheumatology, Radboud University Medical Center; A.B. Blom, PhD, Experimental Rheumatology, Radboud University Medical Center; R.F. Schelbergen, PhD, Experimental Rheumatology, Radboud University Medical Center; M.I. Koenders, PhD, Experimental Rheumatology, Radboud University Medical Center; F.A. van de Loo, PhD, Experimental Rheumatology, Radboud University Medical Center; W.B. van den Berg, PhD, Professor, Experimental Rheumatology, Radboud University Medical Center; T. Vogl, PhD, Professor, Institute of Immunology, University of Muenster; J. Roth, PhD, Professor, Institute of Immunology, University of Münster; P.M. van der Kraan, PhD, Experimental Rheumatology, Radboud University Medical Center; P.L. van Lent, PhD, Experimental Rheumatology, Radboud University Medical Center.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: From Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Immunology, University of Münster, Münster, Germany.M.H. van den Bosch, MSc, Experimental Rheumatology, Radboud University Medical Center; A.B. Blom, PhD, Experimental Rheumatology, Radboud University Medical Center; R.F. Schelbergen, PhD, Experimental Rheumatology, Radboud University Medical Center; M.I. Koenders, PhD, Experimental Rheumatology, Radboud University Medical Center; F.A. van de Loo, PhD, Experimental Rheumatology, Radboud University Medical Center; W.B. van den Berg, PhD, Professor, Experimental Rheumatology, Radboud University Medical Center; T. Vogl, PhD, Professor, Institute of Immunology, University of Muenster; J. Roth, PhD, Professor, Institute of Immunology, University of Münster; P.M. van der Kraan, PhD, Experimental Rheumatology, Radboud University Medical Center; P.L. van Lent, PhD, Experimental Rheumatology, Radboud University Medical Center.
authors.forename: Peter M
authors.initials: PM
authors.lastname: van der Kraan
authors.affiliation: From Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Immunology, University of Münster, Münster, Germany.M.H. van den Bosch, MSc, Experimental Rheumatology, Radboud University Medical Center; A.B. Blom, PhD, Experimental Rheumatology, Radboud University Medical Center; R.F. Schelbergen, PhD, Experimental Rheumatology, Radboud University Medical Center; M.I. Koenders, PhD, Experimental Rheumatology, Radboud University Medical Center; F.A. van de Loo, PhD, Experimental Rheumatology, Radboud University Medical Center; W.B. van den Berg, PhD, Professor, Experimental Rheumatology, Radboud University Medical Center; T. Vogl, PhD, Professor, Institute of Immunology, University of Muenster; J. Roth, PhD, Professor, Institute of Immunology, University of Münster; P.M. van der Kraan, PhD, Experimental Rheumatology, Radboud University Medical Center; P.L. van Lent, PhD, Experimental Rheumatology, Radboud University Medical Center. peter.vanlent@radboudumc.nl.
authors.forename: Peter L
authors.initials: PL
authors.lastname: van Lent
mesh_terms: D040502:Calgranulin B / Q000378:metabolism* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism*
chemical_list: D040502:Calgranulin B; D016207:Cytokines; D020782:Matrix Metalloproteinases
keywords: ALARMINS; M1/M2 MACROPHAGES; OSTEOARTHRITIS; S100A8/A9; SYNOVITIS