Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myeloma tumour growth, except in the most advanced stages of the disease, is restricted to the bone marrow. We used the severe combined immunodeficient-human (SCID-hu) host system, in which primary human myeloma cells grow in, disseminate to and interact with a human microenvironment, to study the interactions between myeloma cells and cells in the bone marrow microenvironment. We used inhibitors of osteoclast activity to determine the role of osteoclasts and their products in supporting myeloma cell growth. Treatment of myelomatous SCID-hu hosts with an inhibitor of osteoclast activity (pamidronate or zoledronate) or with a specific inhibitor of the receptor activator of NF-kappaB ligand (RANKL) halted myeloma-induced bone resorption, when present, and resulted in inhibition of myeloma cell growth and survival. In contrast, myeloma cells from patients with extramedullary disease had a different growth pattern in the SCID-hu hosts and were not inhibited by these interventions, indicating that, while still dependent on a human microenvironment, these cells no longer required the bone marrow microenvironment for survival. This study demonstrates the dependence of myeloma cells on osteoclast activity and their products, and highlights the importance of the myeloma-osteoclast-myeloma loop for sustaining the disease process. Breaking this loop may help control myeloma.
 ...
PMID:Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. 1184 28

Myeloma cells grow only in the bone marrow closely associated with bone,suggesting that this microenvironment provides critical signals for their growth and survival. Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor family, which binds to the ligand for receptor activator of nuclear factor kappa B and inhibits bone resorption. However, it is unclear whether OPG can also bind to other TNF family members, such as TNF-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L), and, by inhibiting their activity, function as a survival factor for myeloma cells. In the present study MG63 osteoblast-like cells and primary bone marrow stromal cells were both shown to produce OPG, whereas human myeloma cells did not produce OPG but down-regulated release of OPG from MG63 cells. TRAIL/Apo2L induced apoptosis in myeloma cells, and this could be prevented with the addition of recombinant OPG. Medium conditioned by MG63 cells was also shown to inhibit TRAIL/Apo2L-induced apoptosis, an effect that was reversed by the addition of soluble receptor activator of nuclear factor kappa B ligand. Medium conditioned by cocultures of MG63 cells with myeloma cells had a reduced effect on TRAIL/Apo2L-induced apoptosis, reflecting the decreased concentrations of OPG in cocultures of myeloma cells with bone cells. These observations suggest that OPG may function as a paracrine survival factor in the bone marrow microenvironment in multiple myeloma.
 ...
PMID:Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells. 1261 2

We have been using the B9/BM1 murine bone marrow metastasis model to study the function of adhesion molecules in the cell-cell interactions and transendothelial migration, necessary for tumor metastasis. The cell surface phenotype of these cells, which colonize vertebral and femoral marrow after intravenous injection, shows great similarity to that of human myeloma cells. In the present study, we investigated the interaction between B9/BM1 cells and osteoclasts, which likely support tumor metastasis in bone marrow. We found that co-culturing B9/BM1 cells and bone marrow-derived endothelial cells (BMECs) in the presence of vitamin D3 and M-CSF promoted differentiation of primary osteoclast progenitors to osteoclasts (detected by TRAP staining), and that this effect was blocked when BMECs were separated from the other cells by a porous polycarbonate membrane. Flow cytometry analysis showed that BMECs expressed RANKL (receptor activator of NF-kappaB ligand) protein on their surface, and that this expression was up-regulated by co-culture with B9/BM1 cells. Accordingly, RT-PCR showed expression of RANKL mRNA also to be up-regulated in BMECs co-cultured with B9/BM1 cells. Addition of OPG (osteoprotegerin, a decoy RANKL receptor) to the co-culture system completely blocked osteoclast induction, as did addition of anti-CD44 antibody. Furthermore, intravenous injection of B9/BM1 cells substantially increased the numbers of TRAP-positive osteoclasts detected in mice in vivo. Taken together, these findings suggest that B9/BM1 myeloma cells act via CD44 to stimulate RANKL expression on BMECs, which in turn physically interact with osteoclast progenitors to promote their differentiation to osteoclasts and metastasis in bone marrow.
 ...
PMID:Bone marrow metastatic myeloma cells promote osteoclastogenesis through RANKL on endothelial cells. 1466 95

The physiological maintenance of bone mass is ensured by bone tissue renewal, allowing old bone tissue to be replaced by an equivalent mass of bone matrix. After mechanical or hormonal stress activation, a phase of resorption by osteoclasts occurs, followed by a phase of bone formation by osteoblasts. Among the multiple factors involved in osteoblastic differentiation are the following: Cbfa1 (transcription factor); low density lipoprotein receptor-related protein-5 (LRP-5), a membrane lipoprotein receptor and protein Wnt co-receptor, which plays an important role during development. It is possible that osteoblastic proliferation and differentiation are regulated by distinct pathways. Osteoclastic differentiation is also regulated by numerous factors: osteoprotegerin (OPG); RANK-L (receptor activator of nuclear factor kappa B ligand, a transmembrane protein related to tumour necrosis factor [TNF], the binding of which to its RANK receptor induces osteoclastic differentiation); and soluble TNF receptors. Local regulation of the OPG/RANK-L ratio could explain postmenopausal loss of bone mass. OPG could play a major role in myeloma and Paget disease. Osteolysis together with bone metastasis could also be related to the local production of RANK-L. OPG decreases osteolysis and offers an interesting therapeutic perspective for the treatment of osteoporosis and other diseases associated with bone hyper-resorption.
 ...
PMID:[Bone remodeling]. 1468 85

The increase of osteoclast activation and formation is mainly involved in the development of the osteolytic bone lesions that characterize multiple myeloma (MM) patients. The mechanisms by which myeloma cells induce bone resorption have not been clear for many years. Recently, new evidence has elucidated which factors are critically involved in the activation of osteoclastic cells in MM. The potential role of the critical osteoclastogenic factor, the receptor activator of NF-kappaB ligand (RANKL), and its soluble antagonist osteoprotegerin (OPG) in the activation of bone resorption in MM is summarized in this review. It has been demonstrated that human MM cells induce an imbalance in the bone marrow environment of the RANKL/OPG ratio in favor of RANKL that triggers the osteoclast formation and activation leading to bone destruction. The direct production of the chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha) by myeloma cells, in combination with the RANKL induction in BM stromal cells in response to myeloma cells, are critical in osteoclast activation and osteoclastogenesis.
 ...
PMID:New insight in the mechanism of osteoclast activation and formation in multiple myeloma: focus on the receptor activator of NF-kappaB ligand (RANKL). 1530 15

The abnomalities in cytokines may be an pathogenetic factor in human diseases as diverse as rheumatoid arthritis (RA), some bone diseases, multiple myeloma, metastatic bone tumors. A cytokine imbalance in favour of pro-inflammatory mediators may be a central pathogenic mechanism in RA. Pro-inflammatory mediators include the cytokines TNF-alpha and IL-1, which activate osteoclasts to resorb subchondral bone. A further important mediator is the recently described osteoclast differentiation factor (ODF) (also reffered to as TNF-related activation-induced cytokine [TRANCE], receptor activator of nuclear factor kappaB ligand [RANKL], or osteoprotegerin ligand).
 ...
PMID:[Inflammatory cytokines and bone diseases]. 1577 37

One of the most characteristic features of multiple myeloma is the development of osteolytic bone lesions. Myeloma-associated bone disease is caused by an increase in osteoclastic bone resorption and a decrease in osteoblastic new bone formation. Insight into the molecular mechanisms of osteoclastogenesis has been provided by the detection of receptor activator of NF-kappaB ligand (RANKL), its specific receptor (RANK) and its decoy receptor antagonist osteoprotegerin (OPG). The RANK signaling system is abnormally regulated in multiple myeloma and targeting this system may ameliorate myeloma bone disease. Less is known about the development of osteoblastic dysfunction, and further knowledge about the interaction between myeloma cells and osteoblasts is required. The aim of this review is to focus on the principles of bone biology for a better understanding of the development of myeloma bone disease and to identify possible therapeutic targets.
 ...
PMID:Identification of new targets for therapy of osteolytic bone disease in multiple myeloma. 1617 2

Bone destruction is a hallmark of multiple myeloma, and recent studies demonstrated a strong interdependence between tumor progression and bone resorption. Increased bone resorption as a major characteristic of multiple myeloma is caused by osteoclast activation and osteoblast inhibition (uncoupling). Myeloma cells alter the local regulation of bone metabolism by increasing the receptor activator of NF-kappaB ligand (RANKL) and decreasing osteoprotegerin (OPG) expression within the bone marrow microenvironment, thereby stimulating the central pathway for osteoclast formation and activation. In addition, they produce the chemokines MIP-1alpha, MIP-1beta and SDF-1alpha, which also increase osteoclast activity. Furthermore, myeloma cells suppress osteoblast function by the secretion of osteoblast inhibiting factors, e.g. Dickkopf (DKK)-1. The resulting bone destruction releases several cytokines, which in turn promote myeloma cell growth. Therefore, the inhibition of bone resorption could stop this vicious circle and not only decrease myeloma bone disease, but also the tumor progression. Preclinical studies provided strong evidence that the suppression of the osteoclast activity using bisphosphonates, RANKL blockade or inhibition of MIP-1alpha or MIP-1beta is effective both in reducing myeloma bone disease and tumor growth and therefore may offer an important treatment strategy in multiple myeloma.
 ...
PMID:Myeloma bone disease. 1618 25

Increased bone resorption is a major characteristic of multiple myeloma and is caused by osteoclast activation and osteoblast inhibition (uncoupling). Myeloma cells alter the local regulation of bone metabolism by increasing the receptor activator of NF-kappaB ligand (RANKL) and decreasing osteoprotegerin expression within the bone marrow microenvironment, thereby stimulating the central pathway for osteoclast formation and activation. In addition, they produce the chemokines MIP-1alpha, MIP-1beta, and SDF-1alpha, which also increase osteoclast activity. On the other hand, myeloma cells suppress osteoblast function by the secretion of osteoblast inhibiting factors, e.g., the Wnt inhibitors DKK-1 and sFRP-2. Moreover, they inhibit differentiation of osteoblast precursors and induce apoptosis in osteoblasts. The resulting bone destruction releases several cytokines, which in turn promote myeloma cell growth. Therefore, the inhibition of bone resorption could stop this vicious circle and not only decrease myeloma bone disease, but also the tumor progression.
 ...
PMID:Novel aspects of osteoclast activation and osteoblast inhibition in myeloma bone disease. 1621 18

Immune and bone cells are functionally coupled by pro-inflammatory cytokine intercellular signaling networks common to both tissues and their crosstalk may contribute to the etiologies of some immune-associated bone pathologies. For example, the receptor activator of NF-kappaB ligand (RANKL)/osteoprotegerin (OPG)/receptor activator of NF-kappaB (RANK) signaling axis plays a critical role in dendritic cell (DC) function as well as bone remodeling. The expression of RANKL by immune cells may contribute to bone loss in periodontitis, arthritis, and multiple myeloma. A recent discovery reveals that DCs release the chromatin protein high mobility group box 1 (HMGB1) as a potent immunomodulatory cytokine mediating the interaction between DCs and T-cells, via HMGB1 binding to the membrane receptor for advanced glycation end products (RAGE). To determine whether osteoblasts or osteoclasts express and/or release HMGB1 into the bone microenvironment, we analyzed tissue, cells, and culture media for the presence of this molecule. Our immunohistochemical and immunocytochemical analyses demonstrate HMGB1 expression in primary osteoblasts and osteoclasts and that both cells express RAGE. HMGB1 is recoverable in the media of primary osteoblast cultures and cultures of isolated osteoclast precursors and osteoclasts. Parathyroid hormone (PTH), a regulator of bone remodeling, attenuates HMGB1 release in cultures of primary osteoblasts and MC3T3-E1 osteoblast-like cells but augments this release in the rat osteosarcoma cell line UMR 106-01, both responses primarily via activation of adenylyl cyclase. PTH-induced HMGB1 discharge by UMR cells exhibits similar release kinetics as reported for activated macrophages. These data confirm the presence of the HMGB1/RAGE signaling axis in bone.
 ...
PMID:HMGB1 expression and release by bone cells. 1641 37


1 2 3 Next >>