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St. Vincent’s Institute of Medical Research and The University of Melbourne, Department of Medicine (R.J.T., J.E., N.J.H., T.J.M., M.T.G.) St. Vincent’s Hospital, Fitzroy, Victoria 3065, Australia; and The Department of Medicine, Division of Endocrinology at the University of Texas Health Science Center, (T.A.G., J.J.Y.) San Antonio, Texas 78284
Address all correspondence and requests for reprints to: Dr. Matthew T. Gillespie, St. Vincent’s Institute of Medical Research, 41 Victoria Parade, Fitzroy 3065, Victoria, Australia. E-mail: m.gillespie{at}medicine.unimelb.edu.au
Breast cancers commonly cause osteolytic metastases in bone, a process
that is dependent upon osteoclast-mediated bone resorption. Recently
the osteoclast differentiation factor (ODF), better termed RANKL
(receptor activator of NF-
B ligand), expressed by osteoblasts has
been cloned as well as its cognate signaling receptor, receptor
activator of NFB (RANK), and a secreted decoy receptor
osteoprotegerin (OPG) that limits RANKL’s biological action. We
determined that the breast cancer cell lines MDA-MB-231, MCF-7, and
T47D as well as primary breast cancers do not express RANKL but express
OPG and RANK. MCF-7, MDA-MB-231, and T47D cells did not act as
surrogate osteoblasts to support osteoclast formation in coculture
experiments, a result consistent with the fact that they do not express
RANKL. When MCF-7 cells overexpressing PTH-related protein (PTHrP) were
added to cocultures of murine osteoblasts and hematopoietic cells,
osteoclast formation resulted without the addition of any osteotropic
agents; cocultures with MCF-7 or MCF-7 cells transfected with pcDNAIneo
required exogenous agents for osteoclast formation. When MCF-7 cells
overexpressing PTHrP were cultured with murine osteoblasts,
osteoblastic RANKL messenger RNA (mRNA) levels were enhanced and
osteoblastic OPG mRNA levels diminished; MCF-7 parental cells had no
effect on RANKL or OPG mRNA levels when cultured with osteoblastic
cells. Using a murine model of breast cancer metastasis to bone, we
established that MCF-7 cells that overexpress PTHrP caused
significantly more bone metastases, which were associated with
increased osteoclast formation, elevated plasma PTHrP concentrations
and hypercalcaemia compared with parental or empty vector controls.
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B. Yi, P. J. Williams, M. Niewolna, Y. Wang, and T. Yoneda Tumor-derived Platelet-derived Growth Factor-BB Plays a Critical Role in Osteosclerotic Bone Metastasis in an Animal Model of Human Breast Cancer Cancer Res., February 1, 2002; 62(3): 917 - 923. [Abstract] [Full Text] [PDF]
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N. Giuliani, R. Bataille, C. Mancini, M. Lazzaretti, and S. Barille Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment Blood, December 15, 2001; 98(13): 3527 - 3533. [Abstract] [Full Text] [PDF]
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R. K. Lindemann, P. Ballschmieter, A. Nordheim, and J. Dittmer Transforming Growth Factor beta Regulates Parathyroid Hormone-related Protein Expression in MDA-MB-231 Breast Cancer Cells through a Novel Smad/Ets Synergism J. Biol. Chem., November 30, 2001; 276(49): 46661 - 46670. [Abstract] [Full Text] [PDF]
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S. Morony, C. Capparelli, I. Sarosi, D. L. Lacey, C. R. Dunstan, and P. J. Kostenuik Osteoprotegerin Inhibits Osteolysis and Decreases Skeletal Tumor Burden in Syngeneic and Nude Mouse Models of Experimental Bone Metastasis Cancer Res., June 1, 2001; 61(11): 4432 - 4436. [Abstract] [Full Text] [PDF]
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 N. J. Horwood, J. Elliott, T. J. Martin, and M. T. Gillespie IL-12 Alone and in Synergy with IL-18 Inhibits Osteoclast Formation In Vitro J. Immunol., April 15, 2001; 166(8): 4915 - 4921. [Abstract] [Full Text] [PDF]
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 G. A. Rodan and T. J. Martin Therapeutic Approaches to Bone Diseases Science, September 1, 2000; 289(5484): 1508 - 1514. [Abstract] [Full Text]
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P. Collin-Osdoby, L. Rothe, F. Anderson, M. Nelson, W. Maloney, and P. Osdoby Receptor Activator of NF-kappa B and Osteoprotegerin Expression by Human Microvascular Endothelial Cells, Regulation by Inflammatory Cytokines, and Role in Human Osteoclastogenesis J. Biol. Chem., June 1, 2001; 276(23): 20659 - 20672. [Abstract] [Full Text] [PDF]
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