| BackgroundBreast cancer is a serious problem which endangers global women's health.It is the most common malignancy with a preference to metastasis to bone,and the chances to develop it are duplicated by obesity.Mechanical loading is one form of physical treatment which imitates human active physical exercise.Our previous studies suggest that ankle loading suppress bone resorption,but their effects on bone metastases of breast cancer have not been investigated.ObjectiveUsing a mouse model with 4T1 cells local injection,we investigated a hypothesis that ankle loading suppresses tumor growth and osteolysis by inhibiting bone resorption and enhancing bone formation in bone metastases of breast cancer.The animals were fed a high-fat diet/control diet before injection of tumor cells,and the animal model of breast cancer bone metastasis was established by local injection of tibia.We investigated a hypothesis that mechanical loading regulates bone marrow stem cell differentiation by inhibiting the differentiation of osteoclasts and bone marrow adipocytes,promoting osteoblasts formation,inhibiting tumor cell growth and invasion,and achieve the purpose of treating bone metastasis of breast cancer.MethodsIn order to explore the effect of mechanical loading on bone microenvironment to treat bone metastases in breast cancer.We fed high-fat diets to mice and control diets in advance to establish different mouse states.Bone metastasis of breast cancer was induced by bilateral intra-tibia injection of mouse breast cancer 4T1 cells in BALB/c female mice.Sixty-five mice were randomized into sham-injected group(sham),model group(M),loading group(L),high fat diet model group(HM)and high fat diet loading group(HML).For mechanical loading,1 N loads were laterally applied to the bilateral ankle at 5 Hz for 3 min/day for 3 weeks.Change in body weight was measured every 5 days.Changes in body weight,body fat,BMI,and BMD of the mice were recorded during the experiment.X-Ray experiment was performed on the mice before the end of the experiment.After three weeks,femur and sacrum were harvested for bone marrow-derived cells to examine osteoclast development,osteoblast differentiation and bone marrow adipocyte differentiation.Establish conditioned medium for bone marrow-derived cells,and the tumor cells were examined by cytology and western blot.Tibias were harvested for histomorphometry,immunohistochemical and western blot to examine bone structure,bone resorption and osteogenesis,as well as tumor growth and invasion in the bone microenvironment.ResultsThe results showed that compared with the sham group,two model groups exhibited the incomplete bone structure in tibia.However,compared to the model group,loading improved the bone structure.For histology-specific staining experiments and bone marrow-derived cells assays,tumor injection activated osteoclast development,bone marrow adipocytes differentiation and suppressed osteoblast formation.Mechanical loading reduced formation,migration,and adhesion of osteoclasts,bone marrow adipocytes differentiation,as well as increased osteoblast formation.Otherwise,model groups increased the tumor bearing,but mechanical loading decreased them in vivo.In addition,cell viability and invasion were examined in vitro to evaluate whether mechanical loading inhibited tumor metastasis.In addition,mechanical loading treated breast cancer bone metastases by changing related proteins.ConclusionIn summary,these results indicated that obesity caused by high-fat diet promotes breast cancer bone metastasis in mice.The effects of mechanical loading might be attributed to suppressing osteoclast development,bone marrow adipocytes differentiation,and increasing osteoblast differentiation by modulating the fate of bone marrow-derived cells.Mechanical loading reduced tumor growth and invasion through bone microenvironment.The current study suggests that ankle loading might potentially be employed as a potential therapy for bone metastases of breast cancer. |
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