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

Research output: Contribution to journalArticle

113 Citations (Scopus)
6 Downloads (Pure)

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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Catenins
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Chondrocytes
Joints
Phenotype
Aggrecans
Differentiation Antigens
Cartilage
Up-Regulation
Cell Proliferation
Pharmacology

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

Cite this

WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways. / Nalesso, Giovanna; Sherwood, Joanna; Bertrand, Jessica; Pap, Thomas; Ramachandran, Manoj; De Bari, Cosimo; Pitzalis, Costantino; Dell'accio, Francesco.

In: Journal of Cell Biology, Vol. 193, No. 3, 05.2011, p. 551-564.

Research output: Contribution to journalArticle

Nalesso, G, Sherwood, J, Bertrand, J, Pap, T, Ramachandran, M, De Bari, C, Pitzalis, C & Dell'accio, F 2011, 'WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways', Journal of Cell Biology, vol. 193, no. 3, pp. 551-564. https://doi.org/10.1083/jcb.201011051
Nalesso, Giovanna ; Sherwood, Joanna ; Bertrand, Jessica ; Pap, Thomas ; Ramachandran, Manoj ; De Bari, Cosimo ; Pitzalis, Costantino ; Dell'accio, Francesco. / WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways. In: Journal of Cell Biology. 2011 ; Vol. 193, No. 3. pp. 551-564.
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