In particular, syndecan-2 deregulated the GSK3 pathway, which may be related to the inhibitory effect of syndecan-2 on the PI3K level, as was previously reported in osteosarcoma cells.15 Wnt ligands secreted by osteoblasts have a crucial role in bone homeostasis.37 Therefore, inhibition of the expression of Wnt target genes, including Wnt ligands and RSPO, likely contributed to the altered microenvironment of osteogenic cells. Here, RSPO1 is linked to osteosarcoma.