title: WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis.
abstract: OBJECTIVE
  Both excessive and insufficient activation of WNT signalling results in cartilage breakdown and osteoarthritis. WNT16 is upregulated in the articular cartilage following injury and in osteoarthritis. Here, we investigate the function of WNT16 in osteoarthritis and the downstream molecular mechanisms.
  
  
  METHODS
  Osteoarthritis was induced by destabilisation of the medial meniscus in wild-type and WNT16-deficient mice. Molecular mechanisms and downstream effects were studied in vitro and in vivo in primary cartilage progenitor cells and primary chondrocytes. The pathway downstream of WNT16 was studied in primary chondrocytes and using the axis duplication assay in Xenopus.
  
  
  RESULTS
  WNT16-deficient mice developed more severe osteoarthritis with reduced expression of lubricin and increased chondrocyte apoptosis. WNT16 supported the phenotype of cartilage superficial-zone progenitor cells and lubricin expression. Increased osteoarthritis in WNT16-deficient mice was associated with excessive activation of canonical WNT signalling. In vitro, high doses of WNT16 weakly activated canonical WNT signalling, but, in co-stimulation experiments, WNT16 reduced the capacity of WNT3a to activate the canonical WNT pathway. In vivo, WNT16 rescued the WNT8-induced primary axis duplication in Xenopus embryos.
  
  
  CONCLUSIONS
  In osteoarthritis, WNT16 maintains a balanced canonical WNT signalling and prevents detrimental excessive activation, thereby supporting the homeostasis of progenitor cells.
authors.affiliation: Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Nalesso
authors.affiliation: Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Bethan Lynne
authors.initials: BL
authors.lastname: Thomas
authors.affiliation: Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.|Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Muenster, Germany.
authors.forename: Joanna Claire
authors.initials: JC
authors.lastname: Sherwood
authors.affiliation: Department of Cell Biology, The Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Medicine & Rheumatology Unit, Rizzoli Orthopaedic Institute, Bologna, Italy.|Department of Biomedical & Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Addimanda
authors.affiliation: Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Suzanne Elizabeth
authors.initials: SE
authors.lastname: Eldridge
authors.affiliation: Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Thorup
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Leslie
authors.initials: L
authors.lastname: Dale
authors.affiliation: Department of Internal Medicine 3, Institute of Clinical Immunology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine 3, Institute of Clinical Immunology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.affiliation: Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.|Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Noha
authors.initials: N
authors.lastname: Eltawil
authors.affiliation: Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.affiliation: Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dell'Accio
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001169:Arthritis, Experimental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology; D051153:Wnt Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000099158:Proteoglycan 4
chemical_list: D011509:Proteoglycans; D012333:RNA, Messenger; D051153:Wnt Proteins; C498837:Prg4 protein, mouse; D000099158:Proteoglycan 4; C585687:Wnt16 protein, mouse
keywords: Chondrocytes; Knee Osteoarthritis; Osteoarthritis