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- Title
WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways.
- Authors
Nalesso, Giovanna; Sherwood, Joanna; Bertrand, Jessica; Pap, Thomas; Ramachandran, Manoj; De Bari, Cosimo; Pitzalis, Costantino; Dell'Accio, Francesca
- 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 dedifferentiation 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 Ca2+/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 Ca2+/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.
- Subjects
WNT proteins; CELL division; CELL proliferation; CARTILAGE; CONNECTIVE tissues; CARTILAGE cells
- Publication
Journal of Cell Biology, 2011, Vol 193, Issue 3, p551
- ISSN
0021-9525
- Publication type
Article
- DOI
10.1083/jcb.201011051