Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment
Open accessAbstract
Although osteolysis is a common complication in patients with multiple myeloma (MM), the biologic mechanisms involved in the pathogenesis of MM-induced bone disease are poorly understood. Two factors produced by stromal-osteoblastic cells seem critical to the regulation of bone resorption: osteoprotegerin (OPG) and its ligand (OPGL). OPGL stimulates osteoclast differentiation and activity, whereas OPG inhibits these processes. The present study investigated whether myeloma cells affect physiologic OPG/OPGL balance in the bone marrow (BM) environment. Ten human myeloma cell lines and myeloma cells isolated from 26 consecutive patients with MM failed to express OPGL and only rarely produced a low amount of OPG. In a coculture system, human myeloma cells up-regulated OPGL expression but strongly down-regulated OPG production in preosteoblastic (preOB) or stromal cells (BMSCs) of primary human BM at the mRNA and protein levels. This effect, which was dependent on cell-to-cell contact between myeloma cells and BMSCs or preOB, partially involved the integrin VLA-4. In addition, overexpression of OPGL mRNA occurred in ex vivo BM cultures obtained from MM patients as compared with healthy donors, and immunohistochemical staining performed on BM biopsy specimens showed an increase of OPGL and a reduction of OPG expression in MM patients as compared with healthy subjects. In summary, these data indicate that myeloma cells affect the OPG/OPGL ratio in the BM environment and tend to confirm that the OPG/OPGL system is involved in the pathogenesis of MM-induced bone disease.
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Multiple myeloma cells up-regulate RANKL expression by bone marrow stromal cells, T cells, and endothelial cells.
“MM cells have been shown to up-regulate RANKL expression by BMSCs (327, 328), by T cells (48), and by endothelial cells (329).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [327]
Breast cancer cells and multiple myeloma cells can down-regulate OPG production by osteoblasts and/or bone marrow stromal cells.
“CaBr cells (101) and MM cells (327, 328, 330) can also down-regulate OPG production by osteoblasts and/or BMSCs.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [327]
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- Authors
- Giuliani, N., Bataille, R., Mancini, C., Lazzaretti, M., & Barillé, S.
- Affiliations
- University of Parma (IT)
- From INSERM U463, Nantes, France; Division of Haematology, Department of Internal Medicine and Biomedical Science, University of Parma, Italy; and the Department of Pathology, University of Parma, Italy.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2001-12-15
- Volume
- 98
- Issue
- 13
- Pages
- 3527-3533
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1999077925
- Cited by
- 415
- References
- 34
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 6 · 2022: 8 · 2021: 12 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 16 · 2016: 11 · 2015: 10 · 2014: 20 · 2013: 21 · 2012: 20
- FWCI
- 9.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Keywords
- multiple myeloma, osteoprotegerin, osteoprotegerin ligand, osteolysis, mesenchymal stem cells, bone resorption, osteoclastogenesis, VLA-4 integrin, bone marrow microenvironment
- MeSH terms
- Aged, Aged, 80 and over, Bone Marrow, Carrier Proteins, Female, Glycoproteins, Humans, Immunohistochemistry, Male, Membrane Glycoproteins, Middle Aged, Multiple Myeloma, Osteoblasts, Osteoclasts, RNA, Messenger, Tumor Cells, Cultured, Gene Expression, Stromal Cells, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Coculture Techniques, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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