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

Giovanna Nalesso¹, Joanna Sherwood¹, Jessica Bertrand¹, Thomas Pap⁴, Manoj Ramachandran², Cosimo De Bari³, Costantino Pitzalis¹, , and Francesco Dell'Accio¹

¹ Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London EC1M6BQ, England, UK
² Department of Orthopaedics, St. Bartholomew’s and The Royal London Hospitals, London E11BBF, England, UK
³ Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
⁴ Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Muenster D-48149, Germany

Correspondence to Francesco Dell’Accio: f.dellaccio{at}qmul.ac.uk

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 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.

Abbreviations: AHAC, adult human articular chondrocyte • FZD, frizzled • GAG, glycosaminoglycan • GPCR, G protein–coupled receptor • LEF, lymphoid enhancer–binding factor • LRP, low-density lipoprotein receptor-related receptor • OA, osteoarthritis • PMA, phorbol 12-myristate 13-acetate • PTX, pertussis toxin • Q-PCR, quantitative PCR • SO, safranin O • TCF, T cell factor

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