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Upregulation of osteoblast apoptosis by malignant plasma cells: a role in myeloma bone disease.
- Source :
-
British journal of haematology [Br J Haematol] 2003 Jul; Vol. 122 (1), pp. 39-52. - Publication Year :
- 2003
-
Abstract
- Typical features of multiple myeloma (MM) are osteolytic lesions and severely affected bone regeneration. This study of 53 MM patients demonstrates an enhancement of osteoblast cytotoxicity by malignant myeloma cells via the upregulation of apoptogenic receptors, including Fas ligand (Fas-L) and tumour-necrosis-factor-related apoptosis inducing ligand (TRAIL). Both were significantly increased in the marrow myeloma cells of patients with extensive osteolytic lesions in a fashion similar to the highly malignant human myeloma cell line MCC-2. Osteoblasts from these subjects over-expressed Fas and death receptor (DR) 4/5 and underwent dramatic apoptosis when co-cultured with either MCC-2 or autologous myeloma cells. In osteoblast and myeloma cell co-cultures, monocyte chemoattractant protein 1 (MCP-1) mRNA was upregulated in osteoblasts from patients with severe bone disease in parallel with increased CC-chemokine receptor R2 (CCR2) expression, the ligand of MCP-1, in the myeloma cells. This chemokine was shown to activate malignant cell migration in vitro. An upregulation of ICAM-1 expression occurred in osteoblasts from patients with active skeleton disease. This upregulation appeared to be an effect of malignant plasma cell contact, as MCC-2 co-culture greatly enhanced ICAM-1 production by resting osteoblasts from patients without skeleton involvement. Our results suggest that osteoblasts in active myeloma are functionally exhausted and promptly undergo apoptosis in the presence of myeloma cells from patients with severe bone disease. It is suggested that this cytotoxic effect plays a pivotal role in the pathogenesis of defective bone repair.
- Subjects :
- Aged
Apoptosis Regulatory Proteins
Chemokine CCL2 metabolism
Coculture Techniques
Fas Ligand Protein
Humans
Intercellular Adhesion Molecule-1 metabolism
Ligands
Membrane Glycoproteins metabolism
Middle Aged
Osteoblasts metabolism
Phenotype
Proteoglycans metabolism
Syndecans
TNF-Related Apoptosis-Inducing Ligand
Tumor Necrosis Factor-alpha metabolism
Up-Regulation
Apoptosis
Multiple Myeloma pathology
Osteoblasts pathology
Plasma Cells physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1048
- Volume :
- 122
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- British journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 12823344
- Full Text :
- https://doi.org/10.1046/j.1365-2141.2003.04374.x