title: WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways.
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 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.
authors.affiliation: Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London EC1M6BQ, England, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Nalesso
authors.forename: Joanna
authors.initials: J
authors.lastname: Sherwood
authors.forename: Jessica
authors.initials: J
authors.lastname: Bertrand
authors.forename: Thomas
authors.initials: T
authors.lastname: Pap
authors.forename: Manoj
authors.initials: M
authors.lastname: Ramachandran
authors.forename: Cosimo
authors.initials: C
authors.lastname: De Bari
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.forename: Francesco
authors.initials: F
authors.lastname: Dell'accio
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D010641:Phenotype; D015398:Signal Transduction; D013552:Swine; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D014981:Xenopus; D029867:Xenopus Proteins; D051176:beta Catenin / Q000378:metabolism
chemical_list: D008024:Ligands; C555506:WNT3A protein, Xenopus; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D029867:Xenopus Proteins; D051176:beta Catenin