Editors' ChoiceDevelopment

Understanding Wnt’s Role in Osteoarthritis

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Science Signaling  10 May 2011:
Vol. 4, Issue 172, pp. ec134
DOI: 10.1126/scisignal.4172ec134

The morphogen Wnt has been implicated in osteoarthritis, which is characterized by the breakdown of joint (articular) cartilage. Contradictory results have been obtained in mouse studies, which showed that both repression and forced activation of Wnt signaling caused chondrodysplasia and osteoarthritis. To better understand these contradictory results, Nalesso et al. turned to cultured articular chondrocytes and found that application of WNT-3A or the Wnt signaling inhibitor DKK1 caused loss of differentiation markers in cultured adult human articular chondrocytes. Wnt signaling can occur through a “canonical” pathway involving stabilization of β-catenin and its translocation to the nucleus to regulate gene expression or through a β-catenin–independent noncanonical pathway involving calcium and calcium-calmodulin kinase II (CaMKII). Detailed analysis of the changes in gene expression showed that inhibition of the canonical pathway with DKK1 inhibited induction of AXIN2 (a marker of the canonical pathway) and PCNA (a marker of proliferating cells) caused by WNT-3A treatment, but treatment with DKK1 failed to rescue the effects of WNT-3A on expression of markers of chondrocyte differentiation: COL2A1, SOX9, and AGGRECAN were reduced both by DKK1 treatment and by WNT-3A treatment, and expression of MMP13 was promoted by either DKK1 or WNT-3A treatment. These results suggested that Wnt signaling may be proceeding through both the canonical and noncanonical pathways, with the canonical pathway regulating proliferative responses and the noncanonical pathway regulating differentiation. Inhibition of the noncanonical pathway by blocking CaMKII activity prevented WNT-3A from inhibiting COL2A1 and SOX9 expression but did not restore proper expression of the MMP13 or AGGRECAN. Dose-response assays with increasing concentrations of WNT-3A showed that at low concentrations, but not high concentrations, of WNT-3A, calcium signaling occurred and was associated with translocation of phosphorylated CaMKII to the nucleus. In contrast, maximal induction of AXIN2, a β-catenin–regulated gene that encodes an inhibitor of the Wnt pathway, was achieved at concentrations of WNT-3A that did not promote calcium signaling. Pharmacological inhibition of CaMKII increased the WNT-3A–mediated induction of AXIN2, and coapplication of WNT-3A and DKK1 produced the greatest increase in calcium signaling, suggesting reciprocal inhibition of the pathways. These results may explain how gradients of Wnt signaling achieve signaling specificity by coupling dose-dependent signaling bias with reciprocal pathway inhibition (see Kestler and Kühl for commentary).

G. Nalesso, J. Sherwood, J. Bertrand, T. Pap, M. Ramachandran, C. De Bari, C. Pitzalis, F. Dell’Accio, WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways. J. Cell Biol. 193, 551–564 (2011). [Abstract] [Full Text]

H. A. Kestler, M. Kühl, Generating a Wnt switch: It’s all about the right dosage. J. Cell Biol. 193, 431–433 (2011). [Abstract] [Full Text]

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