PT  - JOURNAL ARTICLE
AU  - Giovanna Nalesso
AU  - Bethan Lynne Thomas
AU  - Joanna Claire Sherwood
AU  - Jing Yu
AU  - Olga Addimanda
AU  - Suzanne Elizabeth Eldridge
AU  - Anne-Sophie Thorup
AU  - Leslie Dale
AU  - Georg Schett
AU  - Jochen Zwerina
AU  - Noha Eltawil
AU  - Costantino Pitzalis
AU  - Francesco Dell'Accio
TI  - WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis
AID  - 10.1136/annrheumdis-2015-208577
DP  - 2017 Jan 01
TA  - Annals of the Rheumatic Diseases
PG  - 218--226
VI  - 76
IP  - 1
4099  - http://ard.bmj.com/content/76/1/218.short
4100  - http://ard.bmj.com/content/76/1/218.full
SO  - Ann Rheum Dis2017 Jan 01; 76
AB  - 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.