Abstract
Bone metastasis of breast cancer typically leads to osteolysis, which causes severe pathological bone fractures and hypercalcemia. Bone homeostasis is skillfully regulated through osteoblasts and osteoclasts. Bone loss with bone metastasis of breast cancer may be due to both activation of osteoclastic bone resorption and suppression of osteoblastic bone formation. This study was undertaken to determine whether the novel curcumin analogue UBS109 has preventive effects on bone loss induced by breast cancer cell bone metastasis. Nude mice were inoculated with breast cancer MDA-MB-231 bone metastatic cells (106 cells/mouse) into the head of the right and left tibia. One week after inoculation, the mice were treated with control (vehicle), oral administration (p.o.) of UBS109 (50 or 150 mg/kg body weight), or intraperitoneal administration (i.p.) of UBS109 (10 or 20 mg/kg body weight) once daily for 5 days per week for 7 weeks. After UBS109 administration for 7 weeks, hind limbs were assessed using an X-ray diagnosis system and hematoxylin and eosion staining to determine osteolytic destruction. Bone marrow cells obtained from the femurs and tibias were cultured to estimate osteoblastic mineralization and osteoclastogenesis ex vivo and in vitro. Remarkable bone loss was demonstrated in the tibias of mice inoculated with breast cancer MDA-MB-231 bone metastatic cells. This bone loss was prevented by p.o. administration of UBS109 (50 and 150 mg/kg body weight) and i.p. treatment of UBS109 (10 and 20 mg/kg) in vivo. Culture of bone marrow cells obtained from the bone tissues of mice with breast cancer cell bone metastasis showed suppressed osteoblastic mineralization and stimulated osteoclastogenesis ex vivo. These changes were not seen after culture of the bone marrow cells obtained from mice treated with UBS109. Moreover, UBS109 was found to stimulate osteoblastic mineralization and suppress lipopolysaccharide (LPS)-induced osteoclastogenesis in bone marrow cells obtained from normal nude mice in vitro. These findings suggest that the novel curcumin analogue UBS109 prevents breast cancer cell bone metastasis-induced bone loss by stimulating osteoblastic mineralization and suppressing osteoclastogenesis.
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Acknowledgements
Dr. Toshiyuki Yoneda kindly provided breast cancer MDA-MB-231 bone metastatic cells. This study was partly supported by a grant from DOD, US Army, W81XWH-08-1-0494 and NIH/NCI, R21 CA139035-01A2 to M. Shoji.
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All authors have no conflicts of interest.
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The authors (M.Y., M.S.) contributed to the manuscript writing. The authors (M.Y., S.Z., M.S.) contributed to the design, conduct of the study, collection, analysis and interpretation of data. Other authors (S.Z., D.W., J.P.S) contributed to conduct of the study.
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Masayoshi Yamaguchi and Shijun Zhu have equally contributed to this study.
Masayoshi Yamaguchi and Mamoru Shoji have equally contributed as senior authors.
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Yamaguchi, M., Zhu, S., Zhang, S. et al. Curcumin analogue UBS109 prevents bone loss in breast cancer bone metastasis mouse model: involvement in osteoblastogenesis and osteoclastogenesis. Cell Tissue Res 357, 245–252 (2014). https://doi.org/10.1007/s00441-014-1846-4
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DOI: https://doi.org/10.1007/s00441-014-1846-4