A role of TRAIL in killing osteoblasts by myeloma cells.
In multiple myeloma (MM), neoplastic plasma cells accumulate in the bone marrow where their survival, proliferation, and apoptosis are controlled at multiple levels by interaction with the bone marrow microenvironment. Myeloma cells actively control these interactions by activating stromal and endothelial cells for production of survival factors, such as interleukin-6, and suppressing other cell types such as erythroblasts, normal B cell progenitors, and T-cells. In the present study, we identified primary osteoblasts as additional potential targets for myeloma cell-mediated suppression which was partly dependent on the death receptor ligand TRAIL. Besides killing of osteoblasts, myeloma cell lines sensitized osteoblasts to cell death mediated by recombinant TRAIL, whereas primary osteoblasts protected myeloma cells from TRAIL-mediated apoptosis that was mediated by osteoprotegerin (OPG). Besides increase of osteoclastogenesis and osteoclast activity, suppression of bone-forming cells by myeloma cells might contribute to bone loss in MM patients. In addition, clinical development of recombinant TRAIL as anti-myeloma therapy should include evaluation of potential side effects on viability of normal bone cells.
Tinhofer
Inge
I
Laboratory of Immunological and Molecular Cancer Research, 3rd Medical Department of the Salzburg General Hospital and Private Paracelsus Medical University, Salzburg, Austria. i.tinhofer@salk.at
Biedermann
Rainer
R
Krismer
Martin
M
Crazzolara
Roman
R
Greil
Richard
R
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha