Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Upregulation of osteoblast apoptosis by malignant plasma cells: a role in myeloma bone disease. 1282 44

Bone remodelling is severely affected in myeloma bone disease as a consequence of skeletal metastatization of malignant plasma cells. We investigated whether defective bone replacement is dependent on increased osteoblast apoptosis and/or on deregulated events within the bone microenvironment. Circulating tumour necrosis factor (TNF)-alpha, interferon-gamma, interleukin (IL)-1beta, and IL-6 levels were higher in myeloma patients with overt bone disease, whose osteoblasts constitutively overexpressed Fas, DR4/DR5 complex as receptors to TNF-related apoptosis inducing ligand, intercellular adhesion molecule-1 (ICAM-1), and monocyte chemotactic protein-1 (MCP-1). They were functionally exhausted and promptly underwent apoptosis in vitro, in contrast to the minor tendency to death detected in control osteoblasts from patients without bone involvement and normal donors. Osteoblasts dramatically enhanced their apoptosis in co-cultures with MCC-2 myeloma cells and upregulated both ICAM-1 and MCP-1 in a manner similar to control osteoblasts. Pretreating MCC-2 cells with soluble ICAM-1 led to a striking inhibition of their adhesion to osteoblasts, suggesting that the ICAM-1/lymphocyte function-associated antigen-1 system plays a role in the reciprocal membrane contact to trigger apoptogenic signals. Our data suggest that, in the myeloma bone microenvironment, both high cytokine levels and physical interaction of malignant plasma cells with osteoblasts drive the accelerated apoptosis in these cells leading to defective new bone formation.
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PMID:Impaired osteoblastogenesis in myeloma bone disease: role of upregulated apoptosis by cytokines and malignant plasma cells. 1528 39