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XB-ART-43488
J Cell Biol. May 2, 2011; 193 (3): WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways.
Nalesso G
,
Sherwood J
,
Bertrand J
,
Pap T
,
Ramachandran M
,
De Bari C
,
Pitzalis C
,
Dell'accio F
.
Abstract Activation and disruption of Wnt/β-catenin signaling both result in cartilage breakdown via unknown mechanisms. Here we show that both WNT-3A and the Wnt inhibitor DKK1 induced de-differentiation of human articular chondrocytes through simultaneous activation of β-catenin-dependent and independent responses. WNT-3A activates both the β-catenin-dependent canonical pathway and the Ca(2+)/CaMKII noncanonical pathways, with distinct transcriptional targets. WNT-3A promotes cell proliferation and loss of expression of the chondrocyte markers COL2A1, Aggrecan, and SOX9; however, proliferation and AXIN2 up-regulation are downstream of the canonical pathway and are rescued by DKK1, whereas the loss of differentiation markers is CaMKII dependent. Finally, we showed that in chondrocytes, the Ca(2+)/CaMKII-dependent and β-catenin-dependent pathways are reciprocally inhibitory, thereby explaining why DKK1 can induce loss of differentiation through de-repression of the CaMKII pathway. We propose a novel model in which a single WNT can simultaneously activate different pathways with distinct and independent outcomes and with reciprocal regulation. This offers an opportunity for selective pharmacological targeting.Pubmed Id: 21536751 Article link: J Cell Biol.Grant support:
17859 Arthritis Research Campaign, 17971 Arthritis Research Campaign, 19344 Arthritis Research Campaign, G108/620 Medical Research Council Genes referenced: acan axin2 col2a1 dkk1 sox9 wnt3a Antibodies referenced: |
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