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Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells
Therese Standal1, Carina Seidel, Øyvind Hjertner
1Institute of Cancer Research and Molecular Biology, Faculty of Medicine, Norwegian University of Science and Technology, Medisinsk Teknisk Senter, Trondheim, Norway. therese.standal@medisin.ntnu.no
Abstract:
Multiple myeloma (MM) is a hematologic malignancy characterized by accumulation of plasma cells in the bone marrow (BM). Bone destruction is a complication of the disease and is usually associated with severe morbidity. The balance between receptor activator of nuclear factor-kappaB (NF-kappaB) ligand and osteoprotegerin (OPG) is of major importance in bone homeostasis. We have recently shown that serum OPG levels are lower in patients with myeloma than in healthy individuals. Here we show that myeloma cells can bind, internalize, and degrade OPG, thereby providing a possible explanation for the lower levels of OPG in the BM of patients with MM. This process is dependent on interaction of OPG with heparan sulfates on the myeloma cells. The results suggest a novel biologic mechanism for the bone disease associated with MM and that treatment of the bone disease with OPG lacking the heparin-binding domain should be considered.
Insights
Multiple myeloma plasma cells degrade osteoprotegerin (OPG), explaining low OPG levels in patients. This novel mechanism contributes to bone destruction in multiple myeloma (MM).
Area of Science:
- Hematology
- Oncology
- Bone Biology
Background:
- Multiple myeloma (MM) is a cancer of plasma cells, often causing bone destruction and morbidity.
- Bone homeostasis relies on the balance between receptor activator of nuclear factor-kappaB ligand and osteoprotegerin (OPG).
- Previous studies indicated lower serum OPG levels in MM patients compared to healthy individuals.
Purpose of the Study:
- To investigate the mechanism behind reduced osteoprotegerin (OPG) levels in patients with multiple myeloma (MM).
- To elucidate the interaction between myeloma cells and OPG, and its role in bone disease.
Main Methods:
- Investigated the ability of myeloma cells to bind, internalize, and degrade OPG.
- Assessed the role of heparan sulfates on myeloma cells in OPG interaction.
- Analyzed OPG levels in the bone marrow of MM patients.
Main Results:
- Myeloma cells were found to bind, internalize, and degrade OPG.
- This OPG degradation by myeloma cells is dependent on the interaction with heparan sulfates on the cell surface.
- Confirmed lower OPG levels in the bone marrow of MM patients.
Conclusions:
- Myeloma cells actively degrade OPG, providing a mechanism for reduced OPG levels in the bone marrow.
- This interaction represents a novel biologic pathway contributing to the bone disease in multiple myeloma.
- Therapeutic strategies targeting bone disease in MM could involve OPG variants that do not bind to heparin.