Abstract
Activation and disruption of Wnt/ß-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 ß-catenin-dependent and independent responses. WNT-3A activates both the ß-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 ß-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.
Original language | English |
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Pages (from-to) | 551-564 |
Number of pages | 14 |
Journal | Journal of Cell Biology |
Volume | 193 |
Issue number | 3 |
DOIs | |
Publication status | Published - May 2011 |
Keywords
- Animals
- Cartilage, Articular
- Cell Differentiation
- Cells, Cultured
- Chondrocytes
- Ligands
- Mice
- Mice, Nude
- Models, Biological
- Phenotype
- Signal Transduction
- Swine
- Wnt Proteins
- Wnt3 Protein
- Wnt3A Protein
- Xenopus
- Xenopus Proteins
- beta Catenin