Furthermore, although we do not yet have a mechanistic explanation, upregulation of RANKL/OPG ratio and BOKL clustering observed only in direct co-culture with osteo-differentiated BMSCs and not in culture with conditioned medium or in direct co-culture with fibroblasts, further support the hypothesis that heterotypic cell interactions between tumor cells and bone cells can have a key role in the establishment of bone metastases. Here, BOK is linked to neoplasm.