WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways

Giovanna Nalesso, Joanna Sherwood, Jessica Bertrand, Thomas Pap, Manoj Ramachandran, Cosimo De Bari, Costantino Pitzalis, Francesco Dell'accio

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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 languageEnglish
Pages (from-to)551-564
Number of pages14
JournalJournal of Cell Biology
Volume193
Issue number3
DOIs
Publication statusPublished - May 2011

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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

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