title: Rsk2 controls synovial fibroblast hyperplasia and the course of arthritis.
abstract: OBJECTIVE
  Arthritis is a chronic inflammatory disease characterised by immune cell infiltration and mesenchymal cell expansion in the joints. Although the role of immune cells in arthritis is well characterised, the development of mesenchymal cell hyperplasia needs to be better defined. Here, we analysed the role of the ribosomal S6 kinase Rsk2, which we found to be highly activated in joints of patients with arthritis, in the development of mesenchymal cell hyperplasia.
  
  
  METHODS
  We genetically inactivated Rsk2 in the tumour necrosis factor (TNF)-α transgenic (TNFtg) mice, an animal model for human inflammatory arthritis. Clinical and histological signs of arthritis as well as molecular markers of inflammation and joint destruction were quantified. Fibroblast-like synoviocytes (FLS) were characterised in vitro and the effect of Rsk2 deletion on the pattern of gene expression was determined.
  
  
  RESULTS
  Rsk2 deficiency in TNFtg mice results in earlier and exacerbated inflammation as well as increased bone and cartilage destruction. The production of inflammatory cytokines, matrix metalloproteinases and osteoclastogenic molecules was significantly increased in vivo upon Rsk2 inactivation. Bone marrow deficient in Rsk2 could not transfer this phenotype, indicating that Rsk2 expression in mesenchymal cells controls the course of arthritis. Indeed, Rsk2 deficiency was associated with a more activated phenotype and higher proliferative capacity of FLS, thereby increasing cytokines and production of matrix proteinases.
  
  
  CONCLUSIONS
  Rsk2 emerges as a key regulator of mesenchymal cell numbers in the joint and thereby could be targeted to control the inflammatory and tissue-destructive feature of joints in arthritis.
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany Department of Radiation Oncology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Derer
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Böhm
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Grötsch
authors.affiliation: Regine von Ramin Laboratory for Molecular Rheumatology, German Rheumatism Research Center Berlin (DRFZ), An institute of the Leibniz association, Berlin, Germany.
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Grün
authors.affiliation: Regine von Ramin Laboratory for Molecular Rheumatology, German Rheumatism Research Center Berlin (DRFZ), An institute of the Leibniz association, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Grützkau
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stock
authors.affiliation: Department of Biology, Institute of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Sybille
authors.initials: S
authors.lastname: Böhm
authors.forename: Bettina
authors.initials: B
authors.lastname: Sehnert
authors.affiliation: Department of Radiation Oncology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Gaipl
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Axel J
authors.initials: AJ
authors.lastname: Hueber
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany Group Transcription and Gene Expression, Institute of Osteology and Biomechanics (IOBM) University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000502:physiology*; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D020782:Matrix Metalloproteinases
keywords: Bone Mineral Density; Cytokines; Rheumatoid Arthritis; Synovitis; TNF-alpha