Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone.
Open accessAbstract
Prostate cancer (CaP) forms osteoblastic skeletal metastases with an underlying osteoclastic component. However, the importance of osteoclastogenesis in the development of CaP skeletal lesions is unknown. In the present study, we demonstrate that CaP cells directly induce osteoclastogenesis from osteoclast precursors in the absence of underlying stroma in vitro. CaP cells produced a soluble form of receptor activator of NF-kappaB ligand (RANKL), which accounted for the CaP-mediated osteoclastogenesis. To evaluate for the importance of osteoclastogenesis on CaP tumor development in vivo, CaP cells were injected both intratibially and subcutaneously in the same mice, followed by administration of the decoy receptor for RANKL, osteoprotegerin (OPG). OPG completely prevented the establishment of mixed osteolytic/osteoblastic tibial tumors, as were observed in vehicle-treated animals, but it had no effect on subcutaneous tumor growth. Consistent with the role of osteoclasts in tumor development, osteoclast numbers were elevated at the bone/tumor interface in the vehicle-treated mice compared with the normal values in the OPG-treated mice. Furthermore, OPG had no effect on CaP cell viability, proliferation, or basal apoptotic rate in vitro. These results emphasize the important role that osteoclast activity plays in the establishment of CaP skeletal metastases, including those with an osteoblastic component.
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Prostate cancer cells and multiple myeloma cells express RANKL directly.
“prostate cancer cells (CaP) (314 -316) and MM cells (317-322) have been shown to express RANKL directly.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [316]
In that C4-2B intratibial model, OPG also significantly reduced skeletal tumor burden and prevented radiographic bone destruction.
“This therapeutic effect was accompanied by significant reductions in skeletal tumor burden and the prevention of radiographic bone destruction.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [316]
In animal models of prostate cancer spread to bone, lesions often show more osteoclast activity and osteolysis.
“In animal models of prostate cancer metastasis, skeletal lesions frequently exhibit increased osteoclast activation and osteolysis (316,348).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [316]
The reduction in skeletal tumor burden by OPG in the C4-2B model was probably due to suppression of bone turnover.
“which is consistent with the interpretation that OPG reduced skeletal tumor burden via suppression of bone turnover (316).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [316]
OPG is capable of inhibiting osteoclastogenic responses associated with direct RANKL production by cancer cells and in coculture systems where cancer cells induce other cells to express RANKL.
“OPG is capable of inhibiting the osteoclastogenic responses associated with direct RANKL production by cancer cells (317, 332) as well as in coculture systems where cancer cells induce other cells to express RANKL (316,324,329,333).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [316]
OPG did not significantly affect subcutaneous growth of C4-2B tumors.
“OPG treatment had no significant effects on the sc growth of C4 -2B tumors”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [316]
OPG markedly reduced osteoclast numbers in skeletal lesions after intratibial injection of human C4-2B prostate cancer cells into immunodeficient mice.
“OPG treatment was shown to markedly reduce osteoclast numbers in skeletal lesions that resulted from the direct intratibial injection of human C4 -2B prostate cancer cells into immunodeficient mice (316).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [316]
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- Authors
- Zhang, J., Dai, J., Qi, Y., Lin, D.-L., Smith, P., Strayhorn, C., Mizokami, A., Fu, Z., Westman, J., & Keller, E. T.
- Affiliations
- University of Michigan (US)
- Kanazawa University (JP)
- Corresponding author
- Keller, Evan T.
- Venue
- Journal of Clinical Investigation
- Published
- 2001-05-15
- Volume
- 107
- Issue
- 10
- Pages
- 1235-1244
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC209296
- OpenAlex
- W2086008590
- Cited by
- 452
- References
- 43
- Citations by year
- 2026: 3 · 2024: 1 · 2023: 12 · 2022: 5 · 2021: 17 · 2020: 5 · 2019: 13 · 2018: 9 · 2017: 13 · 2016: 13 · 2015: 16 · 2014: 12 · 2013: 22 · 2012: 16
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag015904-05)
- National Institute on Aging (R01AG15904)
- National Cancer Institute (P50-CA-69568, P50CA069568)
- National Center for Research Resources (T32 RR07008, T32RR007008)
- DOD Prostate Cancer Research Program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- osteoprotegerin, prostate cancer, osteoclastogenesis, bone metastasis, RANKL, osteolytic lesions, osteoblastic bone lesions
- MeSH terms
- Animals, Bone Neoplasms, Bone Resorption, Carrier Proteins, Glycoproteins, Humans, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Neoplasm Metastasis, Prostatic Neoplasms, Tibia, Mice, SCID, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Mice, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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