Polyphyllin VII protects from breast cancer-induced osteolysis by suppressing osteoclastogenesis via c-Fos/NFATc1 signaling

Bone is a preferred metastatic site of advanced breast cancer and the 5-year overall survival rate of breast cancer patients with bone metastasis is only 22.8%. Targeted inhibition of osteoclasts can treat skeletal-related events (SREs) in breast cancer patients. Polyphyllin VII (PP7), a pennogenyl saponin isolated from traditional Chinese herb Paris polyphylla, exhibits strong anti-inflammatory and anti-cancer activities. In this study, we evaluated the effect of PP7 on metastatic breast cancer-induced bone destruction in vivo and the underlying mechanisms. We found that intraperitoneal injection of 1 mg/kg PP7 significantly ameliorated the breast cancer MDA-MB-231 cell-induced osteolysis in mice. Mechanistically, PP7 (0.125–0.5 μM) inhibited the conditioned medium of MDA-MB-231 cells (MDA-MB-231 CM)-induced osteoclast formation in bone marrow-derived macrophages (BMMs). Furthermore, PP7 markedly reduced MDA-MB-231 CM-induced osteoclastic bone resorption and F-actin rings formation in vitro. During MDA-MB-231 CM-induced osteoclastogenesis, the activation of c-Fos and NFATc1 signaling was significantly downregulated by PP7, and finally osteoclast-related genes such as Oscar, Atp6v0d2, Mmp9 and β3 integrin were decreased. In addition, the formation of osteoblast was promoted by PP7 treatment. Our current findings revealed PP7 as a potential safe agent for preventing and treating bone destruction in breast cancer patients with bone metastases.