Li, Ke-XinSun, XunLi, Bai-YanYokota, Hiroki2023-03-282023-03-282021-11-09Li KX, Sun X, Li BY, Yokota H. Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells. Cancers (Basel). 2021;13(22):5593. Published 2021 Nov 9. doi:10.3390/cancers13225593https://hdl.handle.net/1805/32081Osteoclasts 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.en-USAttribution 4.0 InternationalCD44Hsp90ab1TGFβWnt signalingBone metastasisBreast cancerEnolase 1iTS cellsOsteoclastsPolyubiquitin CArticle