Bisphosphonates modulate vital functions of human osteoblasts and affect their interactions with breast cancer cells
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Bisphosphonates (BPs) are in clinical use for the treatment of breast cancer patients with bone metastases. Their anti-resorptive effect is mainly explained by inhibition of osteoclast activity, but recent evidence also points to a direct action of BPs on bone-forming osteoblasts. However, the mechanisms how BPs influence osteoblasts and their interactions with breast cancer cells are still poorly characterized. Human osteoblasts isolated from bone specimens were characterized in depth by their expression of osteogenic marker genes. The influence of the nitrogen-containing BPs zoledronate (Zol), ibandronate (Iban), and pamidronate (Pam) on molecular and cellular functions of osteoblasts was assessed focusing on cell proliferation and viability, apoptosis, cytokine secretion, and osteogenic-associated genes. Furthermore, effects of BPs on osteoblast–breast tumor cell interactions were examined in an established in vitro model system. The BPs Zol and Pam inhibited cell viability of osteoblasts. This effect was mediated by an induction of caspase-dependent apoptosis in osteoblasts. By interfering with the mevalonate pathway, Zol also reduces the proliferation of osteoblasts. The expression of phenotypic markers of osteogenic differentiation was altered by Zol and Pam. In addition, both BPs strongly influenced the secretion of the chemokine CCL2 by osteoblasts. Breast cancer cells also responded to Zol and Pam with a reduced cell adhesion to osteoblast-derived extracellular matrix molecules and with a decreased migration in response to osteoblast-secreted factors. BPs revealed prominent effects on human osteoblasts. Zol and Pam as the most potent BPs affected not only the expression of osteogenic markers, osteoblast viability, and proliferation but also important osteoblast–tumor cell interactions. Changing the osteoblast metabolism by BPs modulates migration and adhesion of breast cancer cells as well.
KeywordsOsteoblasts Bisphosphonates Breast cancer Bone metastases Bone marrow microenvironment CCL2/MCP-1
Chemokine, CC motif, ligand 2
Mesenchymal stem cells
Conditioned medium of the osteoblastic cell line CAL72
Poly (ADP-ribose) polymerase 1
Renal cell carcinoma
The authors thank Dr. Bernd Rolauffs (Center for Traumatology, BGU Hospital Tübingen) for his assistance in obtaining the bone specimens and Alice Mager for technical advice and help. This work was supported by a grant of the IZKF program of the Medical Faculty of the University of Tübingen (Grant No. 1686-0-0), by Novartis Pharma AG, Nürnberg, Germany, and by the DFG Graduate School 794. Part of this work was supported by Novartis Pharma AG (Nürnberg, Germany) to TK, GK, TF.
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