Soluble receptor activator of nuclear factor-kB ligand : involvement and significance as therapeutics in the osteolysis associated with breast cancer growth in the bone microenvironment

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Understanding how cancer cells induce bone metastases is essential for the identification of new therapies to control bone metastasis. Using a mouse model that mimics osteolytic changes associated with breast cancer-induced bone metastases, we identified cathepsin G to be proteases that are up-regulated at the tumor bone(TB)-interface. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of receptor activator of nuclear factor-KB ligand(RANKL), generating active soluble version(sRANKL) that is capable of inducing differentiation and activation of osteoclast precursors. The major source of cathepsin G seems to be osteoclasts. Furthermore, we showed that in vivo inhibition of cathepsin G reduces mammary tumor. induced osteolysis.Next we examined the preventive effects of a competitive inhibitor of sRANKL, osteoprotegrin fusion protein(OCIF) was administered to mice before osteolysis induction by implantation of mammary tumor cells(pre), after osteolysis induction(post) or during the entire experimental period(whole). Tumor growth at the TB-interface was significantly suppressed in the pre as well as the post and whole treatment groups of OCIF. The extent of bone destruction was significantly reduced in the pre, post and whole treatment groups. In addition, significantly fewer osteoclasts wereobserved in the OCIF treatment groups regardless of treatment period.Together, our data indicate that inhibition of cathepsin G activity at the TB interface could be therapeutic targets, and sRANKL which is generated by cathepsin G is a potentially target for prevention as well as treatment of breast cancer bone metastasis.