Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells

SIMPLE SUMMARY: Osteoclasts are bone-resorbing cells and, together with bone-forming osteoblasts, they are responsible for maintaining healthy bones. When cancer cells invade into the bone, however, osteoclasts assist in cancer progression and stimulate bone loss. In this study, we converted the bone-destructive action of osteoclasts by activating their Wnt signaling and generated an osteoclast-derived, bone-protective, tumor-suppressive conditioned medium. The conditioned medium was able to suppress tumor growth and bone loss in a mouse model of mammary tumors and bone metastasis. The described approach is expected to add a novel strategy to treat primary breast cancer as well as bone metastasis. ABSTRACT: Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.