The role of osteoclastic activity in prostate cancer skeletal metastases.
Abstract
Metastasis of prostate cancer to bone is a common complication of progressive prostate cancer. Skeletal metastases are often associated with severe pain and thus demand therapeutic interventions. Although often characterized as osteoblastic, prostate cancer skeletal metastases usually have an underlying osteoclastic component. Advances in osteoclast biology and pathophysiology have led toward defining putative therapeutic targets to attack tumor-induced osteolysis. Several factors have been found to be important in tumor-induced promotion of osteoclast activity. One key factor is the protein receptor activator of nuclear factor-kappa B ligand (RANKL), which is required to induce osteoclastogenesis. RANKL is produced by prostate cancer bone metastases, enabling these metastases to induce osteolysis through osteoclast activation. Another factor, osteoprotegerin, is a soluble decoy receptor for RANKL and inhibits RANKL-induced osteoclastogenesis. Osteoprotegerin has been shown in murine models to inhibit tumor-induced osteolysis. In addition to RANKL, parathyroid hormone-related protein and interleukin-6 are produced by prostate cancer cells and can promote osteoclastogenesis. Finally, matrix metalloproteinases (MMPs) are secreted by prostate cancer cells and promote osteolysis primarily through degradation of the nonmineralized bone matrix. MMP inhibitors have been shown to diminish tumor establishment in bone in murine models. Thus, many factors derived from prostate cancer metastases can promote osteolysis, and these factors may serve as therapeutic targets. The importance of osteoclasts in the establishment and progression of skeletal metastases has led to clinical evaluation of therapeutic agents to target them for slowing metastatic progression. Bisphosphonates are a class of compounds that decrease osteoclast life span by promoting their apoptosis. The bisphosphonate pamidronate has proven clinical efficacy for relieving bone pain associated with breast cancer metastases and has a promising outlook for prostate cancer metastases. Another bisphosphonate, zoledronic acid, appears to directly target prostate cancer cells in addition to diminishing osteoclast activity at the metastatic site. In addition to bisphosphonates, other novel therapies based on studies that delineate mechanisms of skeletal metastases establishment and progression will be developed in the near future.
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Prostate cancer bone metastases usually look osteoblastic, yet bone resorption is often raised in these lesions.
“While bone metastasis lesions in prostate cancer patients typically have an osteoblastic (osteosclerotic) appearance, there is evidence that bone resorption is also frequently increased in these lesions (346,347).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [347]
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- Authors
- Keller, E. T.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Keller, E.T.
- ORCID
- Keller, E.T.
- Venue
- Drugs of Today
- Publisher
- Portico
- Published
- 2002
- Volume
- 38
- Issue
- 2
- Pages
- 91
- ISSN
- 0025-7656 (ISSN-L)
- 1699-4019
- OpenAlex
- W2087016656
- Cited by
- 55
- References
- 0
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2019: 3 · 2018: 1 · 2014: 1 · 2013: 3
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drugs of today (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P50-CA-69568, P50CA069568)
- 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
- prostate cancer, bone metastasis, osteoclasts, tumor-induced osteolysis, RANKL, osteoprotegerin, osteoclastogenesis, parathyroid hormone-related protein, interleukin-6, matrix metalloproteinases, bisphosphonates, pamidronate, zoledronic acid, bone pain, therapeutic target
- MeSH terms
- Animals, Bone Neoplasms, Carrier Proteins, Humans, Male, Membrane Glycoproteins, Osteoclasts, Osteolysis, Prostatic Neoplasms, Interleukin-6, Matrix Metalloproteinases, Peptide Hormones, Parathyroid Hormone-Related Protein, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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