title: Upregulation of osteoblast apoptosis by malignant plasma cells: a role in myeloma bone disease.
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.
authors.affiliation: Department of Internal Medicine and Oncology (DIMO), University of Bari, Bari, Italy. f.silvestris@dio.uniba.it
authors.forename: Franco
authors.initials: F
authors.lastname: Silvestris
authors.forename: Paola
authors.initials: P
authors.lastname: Cafforio
authors.forename: Marco
authors.initials: M
authors.lastname: Tucci
authors.forename: Daniela
authors.initials: D
authors.lastname: Grinello
authors.forename: Franco
authors.initials: F
authors.lastname: Dammacco
mesh_terms: D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D018932:Chemokine CCL2 / Q000378:metabolism; D018920:Coculture Techniques; D053222:Fas Ligand Protein; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology*; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D010950:Plasma Cells / Q000502:physiology*; D011509:Proteoglycans / Q000378:metabolism; D053667:Syndecans; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D018932:Chemokine CCL2; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D053667:Syndecans; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1