WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis

Nalesso, Giovanna; Thomas, B.L.; Sherwood, J.; Yu, Jing; Addimanda, Olga; Eldridge, S.; Thorup, Anne-Sophie; Dale, Leslie; Schett, Georg; Zwerina, Jochen; Eltawil, N.M.; Pitzalis, Costantino; Dell’Accio, Francesco

doi:10.1136/annrheumdis-2015-208577

Cited by 115 publications

(137 citation statements)

References 37 publications

Supporting

Mentioning

128

Contrasting

Order By: Relevance

“…However, Nalesso et al 38 showed that while WNT16 was capable of binding Fzd receptors and activating canonical WNT signaling, the degree of activation was significantly lower when compared with the more abundant WNT3A. TOPFlash assays showed that costimulation with both WNT3A and WNT16 resulted in significantly less canonical WNT activation when compared with stimulation using WNT3A alone 38 . Thus, it appears WNT16 acts as a competitive inhibitor of Fzd and acts to ensure the homeostasis of WNT signaling.…”

Section: Discussionmentioning

confidence: 99%

APCMutation marks an aggressive subtype ofBRAFmutant colorectal cancers

Fennell

Kane

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractBackground & AimsWNT activation is a hallmark of colorectal cancer. BRAF mutation is present in 15% of colorectal cancers, and the role of mutations in WNT signaling regulators in this context is unclear. Here we evaluate the mutational landscape of WNT signaling regulators in BRAF mutant cancers.MethodsWe performed exome-sequencing on 24 BRAF mutant colorectal cancers and analysed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled, in vivo, using the Apcmin/+ and BrafV637/Villin-CreERT2/+mouse, respectively.ResultsRNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade, including MEN1, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (P< 2×10−5), advanced stage (P<0.01), and poor survival (P=0.026). Apcmin/+/BrafV637 animals had more numerous and larger SI and colonic lesions (P<0.0001 and P<0.05, respectively), and a markedly reduced survival (Median survival: 3.2 months, P=8.8×10−21) compared to animals with Apc or Braf mutation alone.ConclusionsThe WNT signaling axis is frequently mutated in BRAF mutant colorectal cancers. WNT16 and MEN1 may be novel drivers of aberrant WNT signaling in colorectal cancer. Co-mutation of BRAF and APC generates an extremely aggressive neoplastic phenotype that is associated with poor patient outcome.SynopsisWe have comprehensively evaluated the somatic mutation landscape of WNT signaling regulators in serrated colorectal cancers. We identified a mosaic of mutations that may be responsible for elevating WNT signaling in this context. Approximately 20% of serrated colorectal cancers harbor truncating APC mutation, and these cancers confer extremely poor prognoses.

show abstract

Section: Discussionmentioning

confidence: 99%

APCMutation marks an aggressive subtype ofBRAFmutant colorectal cancers

Fennell

Kane

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…A similar function has recently been described for WNT16. Nalesso et al 34. suggest that WNT16 prevents excessive Wnt activation in articular cartilage by acting as a partial agonist of this cascade, thereby competing for receptor binding with a full agonist.…”

Section: Discussionmentioning

confidence: 99%

DOT1L safeguards cartilage homeostasis and protects against osteoarthritis

et al. 2017

View full text Add to dashboard Cite

Osteoarthritis is the most prevalent and crippling joint disease, and lacks curative treatment, as the underlying molecular basis is unclear. Here, we show that DOT1L, an enzyme involved in histone methylation, is a master protector of cartilage health. Loss of DOT1L disrupts the molecular signature of healthy chondrocytes in vitro and causes osteoarthritis in mice. Mechanistically, the protective function of DOT1L is attributable to inhibition of Wnt signalling, a pathway that when hyper-activated can lead to joint disease. Unexpectedly, DOT1L suppresses Wnt signalling by inhibiting the activity of sirtuin-1 (SIRT1), an important regulator of gene transcription. Inhibition of SIRT1 protects against osteoarthritis triggered by loss of DOT1L activity. Modulating the DOT1L network might therefore be a therapeutic approach to protect the cartilage against osteoarthritis.

show abstract

“…We have shown in zebrafish that wnt16 is downstream of mechanical strains in the developing joint, and controls chondrocyte proliferation and migration. Wnt16 is also linked to hip geometry (74) altered cortical bone thickness (75,76) the response of chondrocytes to injury and to osteoarthritis (77,78).…”

Section: Discussionmentioning

confidence: 99%

The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early onset osteoarthritis

Lawrence

Kague

Aggleton

et al. 2018

Preprint

View full text Add to dashboard Cite

(max 200 words)Collagen is the major structural component of cartilage and mutations in the genes encoding Type XI collagen are associated with severe skeletal dysplasias (Fibrochondrogenesis and Stickler syndrome) and early onset osteoarthritis. The impact of the lack of Type XI collagen on cell behaviour and mechanical performance during skeleton development is unknown. We studied a zebrafish mutant for col11a2 and evaluated cartilage, bone development and mechanical properties to address this. We show that in col11a2 mutants Type II collagen is made but is prematurely degraded in maturing cartilage and ectopically expressed in the joint. These changes are correlated with increased stiffness of both bone and cartilage; quantified using Atomic Force Microscopy. In the mutants, the skeletal rudiment terminal region in the jaw joint are broader and the interzone smaller. These differences in shape and material properties impact on joint function and mechanical performance, which we modelled using Finite Element Analyses. Finally, we show that col11a2 heterozygous carriers reach adulthood but show signs of severe early onset osteoarthritis. Taken together our data demonstrate a key role for Type XI collagen in maintaining the properties of cartilage matrix; which when lost leads to alterations to cell behaviour that give rise to joint pathologies.

show abstract

WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis

Cited by 115 publications

References 37 publications

APCMutation marks an aggressive subtype ofBRAFmutant colorectal cancers

APCMutation marks an aggressive subtype ofBRAFmutant colorectal cancers

DOT1L safeguards cartilage homeostasis and protects against osteoarthritis

The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early onset osteoarthritis

Contact Info

Product

Resources

About