The role of Dkk-1 in human osteosarcoma and its regulation

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Wnt signalling has been shown to be important for regulating osteoblast activity and thus producing and maintaining adequate bone mass. Dkk-1 is a secreted inhibitor of Wnt signalling and is a key intermediary causing bone erosion in a model of rheumatoid arthritis. Dkk-1 is also reported to be necessary to enable mesenchymal stem cells (MSC) to enter the cell cycle. If MSCs are cultured with Dkk-1 they can become tumourigenic and, conversely, a mesenchymally-derived tumour in which Wnt signalling was re-established, has been shown to be capable of differentiation into osteogenic and adipogenic lineages. Thus, it was suggested that Dkk-1 is pro-oncogenic and Wnt signalling serves as a tumour suppressor in human MSC. We hypothesised that Dkk-1 would be important for the survival of other mesenchymally derived tumours and so we examined two human osteosarcoma cell lines (MG63 and Saos2) showing different degrees of similarity to the osteoblastic phenotype for expression of Dkk-1 in response to various growth factors. The less differentiated cell line (MG63) produced 4 times as much Dkk-1 as Saos2 when cells were confluent as measured by ELISA. Both cell lines showed up-regulation of Dkk-1 in response to members of the TGF superfamily, BMP2 and 7, TGFbeta and activin A, though to different extents. TNFalpha and PDGF also stimulated Dkk-1 production, signalling through PKC and ERK, as demonstrated by specific inhibitors. On the other hand, acidic FGF and IGFII inhibited Dkk-1 production. This is the first stage of a project which will go on to measure by quantitative PCR, Wnt expression, and then use siRNA to investigate the effects of inhibiting Dkk-1 expression. These responses imply that these two osteosarcoma cell lines are amenable to modulation of Wnt signalling which may impact on their differentiation state and proliferative capacity. This may have implications for the treatment of osteosarcoma.