title: A homeostatic function of CXCR2 signalling in articular cartilage.
abstract: OBJECTIVE
  ELR+ CXC chemokines are heparin-binding cytokines signalling through the CXCR1 and CXCR2 receptors. ELR+ CXC chemokines have been associated with inflammatory arthritis due to their capacity to attract inflammatory cells. Here, we describe an unsuspected physiological function of these molecules in articular cartilage homeostasis.
  
  
  METHODS
  Chemokine receptors and ligands were detected by immunohistochemistry, western blotting and RT-PCR. Osteoarthritis was induced in wild-type and CXCR2(-/-) mice by destabilisation of the medial meniscus (DMM). CXCR1/2 signalling was inhibited in vitro using blocking antibodies or siRNA. Chondrocyte phenotype was analysed using Alcian blue staining, RT-PCR and western blotting. AKT phosphorylation and SOX9 expression were upregulated using constitutively active AKT or SOX9 plasmids. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay.
  
  
  RESULTS
  CXCL6 was expressed in healthy cartilage and was retained through binding to heparan sulfate proteoglycans. CXCR2(-/-) mice developed more severe osteoarthritis than wild types following DMM, with increased chondrocyte apoptosis. Disruption of CXCR1/2 in human and CXCR2 signalling in mouse chondrocytes led to a decrease in extracellular matrix production, reduced expression of chondrocyte differentiation markers and increased chondrocyte apoptosis. CXCR2-dependent chondrocyte homeostasis was mediated by AKT signalling since forced expression of constitutively active AKT rescued the expression of phenotypic markers and the apoptosis induced by CXCR2 blockade.
  
  
  CONCLUSIONS
  Our study demonstrates an important physiological role for CXCR1/2 signalling in maintaining cartilage homeostasis and suggests that the loss of ELR+ CXC chemokines during cartilage breakdown in osteoarthritis contributes to the characteristic loss of chondrocyte phenotypic stability.
authors.affiliation: Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Muenster, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Sherwood
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Muenster, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bertrand
authors.affiliation: Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Nalesso
authors.affiliation: Division of Medicine, Centre for Rheumatology and Connective Tissue Disease, UCL, London, UK.
authors.forename: Blandine
authors.initials: B
authors.lastname: Poulet
authors.affiliation: Department of Veterinary Basic Sciences, Royal Veterinary College, University of London, Royal College Street, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Pitsillides
authors.affiliation: Dompé S.P.A., L'Aquila, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Brandolini
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Karystinou
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, UK.
authors.forename: Cosimo
authors.initials: C
authors.lastname: De Bari
authors.affiliation: Skeletal Biology and Engineering Research Center, KU Leuven, Belgium.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Luyten
authors.affiliation: Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pap
authors.affiliation: Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dell'Accio
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010003:Osteoarthritis / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D023063:Receptors, Interleukin-8B
keywords: Chemokines; Chondrocytes; Osteoarthritis