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J Cell Biol May 2, 2011; 193 (3): 551-64.

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 .

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
PMC ID: PMC3087013
Article link: J Cell Biol
Grant support: [+]

Species referenced: Xenopus
Genes referenced: acan actl6a axin2 camk2g col2a1 ctnnb1 dkk1 mmp13 pcna sox9 wnt3a

Article Images: [+] show captions
References [+] :
Akiyama, Interactions between Sox9 and beta-catenin control chondrocyte differentiation. 2004, Pubmed, Xenbase