Preclinical evaluation of zoledronate using an in vitro mimetic cellular model for breast cancer metastatic bone disease
(2013) In Biochimica et Biophysica Acta - General Subjects 1830(6). p.3625-3634- Abstract
Background The interactions between metastatic breast cancer cells and host cells of osteoclastic lineage in bone microenvironment are essential for osteolysis. In vitro studies to evaluate pharmacological agents are mainly limited to their direct effects on cell lines. To mimic the communication between breast cancer cells and human osteoclasts, a simple and reproducible cellular model was established to evaluate the effects of zoledronate (zoledronic acid, ZOL), a bisphosphonate which exerts antiresorptive properties. Methods Human precursor osteoclasts were cultured on bone-like surfaces in the presence of stimuli (sRANKL, M-CSF) to ensure their activation. Furthermore, immature as well as activated osteoclasts were co-cultured with... (More)
Background The interactions between metastatic breast cancer cells and host cells of osteoclastic lineage in bone microenvironment are essential for osteolysis. In vitro studies to evaluate pharmacological agents are mainly limited to their direct effects on cell lines. To mimic the communication between breast cancer cells and human osteoclasts, a simple and reproducible cellular model was established to evaluate the effects of zoledronate (zoledronic acid, ZOL), a bisphosphonate which exerts antiresorptive properties. Methods Human precursor osteoclasts were cultured on bone-like surfaces in the presence of stimuli (sRANKL, M-CSF) to ensure their activation. Furthermore, immature as well as activated osteoclasts were co-cultured with MDA-MB-231 breast cancer cells. TRAP5b and type I collagen N-terminal telopeptide (NTx) were used as markers. Osteoclasts' adhesion to bone surface and subsequent bone breakdown were evaluated by studying the expression of cell surface receptors and certain functional matrix macromolecules in the presence of ZOL. Results ZOL significantly suppresses the precursor osteoclast maturation, even when the activation stimuli (sRANKL and M-SCF) are present. Moreover, it significantly decreases bone osteolysis and activity of MMPs as well as precursor osteoclast maturation by breast cancer cells. Additionally, ZOL inhibits the osteolytic activity of mature osteoclasts and the expression of integrin β3, matrix metalloproteinases and cathepsin K, all implicated in adhesion and bone resorption. Conclusions ZOL exhibits a beneficial inhibitory effect by restricting activation of osteoclasts, bone particle decomposition and the MMP-related breast cancer osteolysis. General significance The proposed cellular model can be reliably used for enhancing preclinical evaluation of pharmacological agents in metastatic bone disease.
(Less)
- author
- Dedes, P. G. ; Kanakis, I. ; Gialeli, Ch LU ; Theocharis, A. D. ; Tsegenidis, T. ; Kletsas, D. ; Tzanakakis, G. N. and Karamanos, N. K.
- publishing date
- 2013-06
- type
- Contribution to journal
- publication status
- published
- keywords
- Bone metastasis, Breast cancer, Cellular model, Matrix macromolecule, Metalloproteinase
- in
- Biochimica et Biophysica Acta - General Subjects
- volume
- 1830
- issue
- 6
- pages
- 3625 - 3634
- publisher
- Elsevier
- external identifiers
-
- pmid:23395844
- scopus:84876004427
- ISSN
- 0304-4165
- DOI
- 10.1016/j.bbagen.2013.01.020
- language
- English
- LU publication?
- no
- id
- 14b5e3f8-d359-4fd1-9320-6f89cff26237
- date added to LUP
- 2024-04-03 21:47:43
- date last changed
- 2024-04-22 15:30:13
@article{14b5e3f8-d359-4fd1-9320-6f89cff26237,
abstract = {{<p>Background The interactions between metastatic breast cancer cells and host cells of osteoclastic lineage in bone microenvironment are essential for osteolysis. In vitro studies to evaluate pharmacological agents are mainly limited to their direct effects on cell lines. To mimic the communication between breast cancer cells and human osteoclasts, a simple and reproducible cellular model was established to evaluate the effects of zoledronate (zoledronic acid, ZOL), a bisphosphonate which exerts antiresorptive properties. Methods Human precursor osteoclasts were cultured on bone-like surfaces in the presence of stimuli (sRANKL, M-CSF) to ensure their activation. Furthermore, immature as well as activated osteoclasts were co-cultured with MDA-MB-231 breast cancer cells. TRAP5b and type I collagen N-terminal telopeptide (NTx) were used as markers. Osteoclasts' adhesion to bone surface and subsequent bone breakdown were evaluated by studying the expression of cell surface receptors and certain functional matrix macromolecules in the presence of ZOL. Results ZOL significantly suppresses the precursor osteoclast maturation, even when the activation stimuli (sRANKL and M-SCF) are present. Moreover, it significantly decreases bone osteolysis and activity of MMPs as well as precursor osteoclast maturation by breast cancer cells. Additionally, ZOL inhibits the osteolytic activity of mature osteoclasts and the expression of integrin β3, matrix metalloproteinases and cathepsin K, all implicated in adhesion and bone resorption. Conclusions ZOL exhibits a beneficial inhibitory effect by restricting activation of osteoclasts, bone particle decomposition and the MMP-related breast cancer osteolysis. General significance The proposed cellular model can be reliably used for enhancing preclinical evaluation of pharmacological agents in metastatic bone disease.</p>}},
author = {{Dedes, P. G. and Kanakis, I. and Gialeli, Ch and Theocharis, A. D. and Tsegenidis, T. and Kletsas, D. and Tzanakakis, G. N. and Karamanos, N. K.}},
issn = {{0304-4165}},
keywords = {{Bone metastasis; Breast cancer; Cellular model; Matrix macromolecule; Metalloproteinase}},
language = {{eng}},
number = {{6}},
pages = {{3625--3634}},
publisher = {{Elsevier}},
series = {{Biochimica et Biophysica Acta - General Subjects}},
title = {{Preclinical evaluation of zoledronate using an in vitro mimetic cellular model for breast cancer metastatic bone disease}},
url = {{http://dx.doi.org/10.1016/j.bbagen.2013.01.020}},
doi = {{10.1016/j.bbagen.2013.01.020}},
volume = {{1830}},
year = {{2013}},
}