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

Myeloma bone disease is due to bone degradation by osteoclasts, and absence of repair by bone forming osteoblasts. Recent observations suggest that the anti-myeloma drug bortezomib, a proteasome inhibitor, stimulates bone formation and may inhibit bone resorption. Here, we tested bortezomib on cultured osteoclasts in conditions mimicking the pulse treatment used in the clinic, thereby avoiding continuous proteasome inhibition and unselective toxicity. A 3 h pulse with 25 nM bortezomib followed by a 3-day culture in its absence markedly inhibited osteoclast activity as evaluated through bone resorption, TRAcP release, and RANKL-induced NF-kappaB translocation into nuclei, an event dependent on proteasomes and critical for osteoclast function. The effect on TRAcP was maximal during the first 24 h post-pulse, and then tended to subside. Importantly, applying this pulse treatment to cultured myeloma cells drastically reduced their survival. We measured next the levels of two bone resorption markers in patients during the 3 days following five and seven therapeutic bortezomib administrations, respectively. These levels decreased significantly already 1-2 days after injection, and then increased, showing temporary inhibition of osteoclast activity and paralleling the in vitro effect on TRAcP. Our study demonstrates a direct inhibition of osteoclasts by bortezomib in conditions relevant to treatment of myeloma.
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PMID:Pulse treatment with the proteasome inhibitor bortezomib inhibits osteoclast resorptive activity in clinically relevant conditions. 1861 29

Patients with multiple myeloma (MM) experience pathologic fractures, bone pain, hypercalcemia, neurologic symptoms, and renal insufficiency with substantial morbidity and mortality. Bisphosphonates have been used successfully for the management of MM-related bone disease. Increased incidence of osteonecrosis of the jaw has been observed in patients with cancer receiving bisphosphonate therapy. Recent advances in the pathobiology of MM-related bone disease and other cancer-related bone metastases have led to the identification of novel therapeutic targets, such as receptor activator of nuclear factor-kappaB (RANK); its ligand (RANKL); and a decoy receptor, osteoprotegerin, for the development of potential targeted agents. Initials studies have demonstrated that targeting RANK/ RANKL signaling with the fully human monoclonal antibody denosumab prevented skeletal complications in patients with MM and other cancers with bone metastases. Ongoing studies evaluating the clinical utility of denosumab in cancer- related bone destruction have been discussed. In addition, several potential targets, such as macrophage inflammatory protein-1alpha, chemokine receptors 1 and 5, interleukin-3, and Wnt signaling, are b riefly described.
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PMID:Novel approaches in the management of myeloma-related skeletal complications. 1863 61

Multiple myeloma (MM) is a plasma cell malignancy characterized by a high capacity to induce osteolytic bone lesions. MM patients with osteolytic bone lesions have lower numbers of osteoblasts and decreased bone formation, which plays a critical role in the bone-destructive process. Although the mechanism of estrogen action on bone cells and myeloma cells has been widely investigated, estrogen action on bone cells in MM is unknown. In this study, the effects of the gonadal hormone 17beta-estradiol on cell growth, alkaline phosphatase (ALP) activity, mineralization capacity, and RANKL/OPG ratios in primary rat osteoblasts cultured with MM cell conditioned medium (CM) or co-cultured with RPMI8226 cells were investigated. Treatments of 10(-2) to 10 nM 17beta-estradiol reversed inhibition of proliferation and ALP activity of osteoblasts by myeloma cells in a dose-dependent manner, and 10(-2) to 1 nM 17beta-estradiol reversed inhibition of the mineralization capacity of osteoblasts by myeloma cells. In co-culture experiments with primary rat osteoblasts and myeloma cells, treatments of 10(-2) to 10 nM 17beta-estradiol down-regulated transcription and secretion of RANKL and up-regulated transcription and secretion of OPG in the osteoblasts, reversing the effects of co-cultured myeloma cells. These findings suggest that 17beta-estradiol may temper the inhibitory effects of myeloma cells on osteoblasts and improve RANKL/OPG balance, providing a new agent for treatment of bone disease in myeloma.
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PMID:17beta-Estradiol overcomes human myeloma RPMI8226 cell suppression of growth, ALP activity, and mineralization in rat osteoblasts and improves RANKL/OPG balance in vitro. 1916 63

Receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) has emerged as a major mediator of bone resorption, commonly associated with cancer and other chronic inflammatory diseases. Inhibitors of RANKL signaling thus have potential in preventing bone loss. In the present report, the potential of zerumbone, a sesquiterpene derived from subtropical ginger, to modulate osteoclastogenesis induced by RANKL and breast cancer was examined. We found that zerumbone inhibited RANKL-induced NF-kappaB activation in mouse monocyte, an osteoclast precursor cell, through inhibition of activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, and IkappaBalpha degradation. Zerumbone also suppressed RANKL-induced differentiation of these cells to osteoclasts. This sesquiterpene also inhibited the osteoclast formation induced by human breast tumor cells and by multiple myeloma cells. Finally, we examined whether zerumbone could prevent human breast cancer-induced bone loss in animals. We found that zerumbone decreased osteolysis in a dose-dependent manner in MDA-MB-231 breast cancer tumor-bearing athymic nude mice. These results indicate that zerumbone is an effective blocker of RANKL-induced NF-kappaB activation and of osteoclastogenesis induced by RANKL and tumor cells, suggesting its potential as a therapeutic agent for osteoporosis and cancer-associated bone loss.
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PMID:Zerumbone abolishes RANKL-induced NF-kappaB activation, inhibits osteoclastogenesis, and suppresses human breast cancer-induced bone loss in athymic nude mice. 3018 10

Proteasome inhibitors represent a promising therapy for the treatment of relapsed and/or refractory multiple myeloma, a disease that is concomitant with osteolysis and enhanced osteoclast formation. While blockade of the proteosome pathway has been recently shown to influence osteoclast formation and function, the precise molecular cascade underlying these effects is presently unclear. Here, we provide evidence that proteasome inhibitors directly impair osteoclast formation and function via the disruption of key RANK-mediated signaling cascades. Disruption of the proteosome pathway using selective inhibitors (MG-132, MG-115, and epoxomicin) resulted in the accumulation of p62 and CYLD, and altered the subcellular targeting and distribution of p62 and TRAF6 in osteoclast-like cells. Proteosome inhibition also blocked RANKL-induced NF-kappaB activation, IkappaBalpha degradation and nuclear translocation of p65. The disruption in RANK-signaling correlated dose-dependently with an impairment in osteoclastogenesis, with relative potency epoxomicin > MG-132 > MG-115 based on equimolar concentrations. In addition, these inhibitors were found to impact osteoclastic microtubule organization and attenuate bone resorption. Based on these data we propose that deregulation of key RANK-mediated signaling cascades (p62, TRAF6, CYLD, and IkappaBalpha) underscores proteasome-mediated inhibition of osteolytic bone conditions.
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PMID:Proteasome inhibitors impair RANKL-induced NF-kappaB activity in osteoclast-like cells via disruption of p62, TRAF6, CYLD, and IkappaBalpha signaling cascades. 1936 10

Decoy receptor 3 (DcR3), a member of the tumor necrosis factor (TNF) receptor superfamily, is known to be involved in cell survival and osteoclast (OC) formation. In this study, we show that malignant plasma cells and T lymphocytes from multiple myeloma (MM) bone disease patients, as well as Karpas 909, a human myeloma cell line, directly produce DcR3. By interacting with FasL, this molecule could inhibit OC apoptosis. In fact, the use of a neutralizing anti-DcR3 antibody induces a reduction of cell viability with a consequent increase of apoptotic cell number, the activation of caspase-8 and -3, and DNA fragmentation. Furthermore, we show that DcR3 supports OC formation in samples from MM patients through the upregulation of RANKL and TNFalpha by T lymphocytes and only TNFalpha by CD14+ cells. In conclusion, our data provide the first evidence of the expression of DcR3 in MM, and the involvement of this molecule in supporting the survival and formation of OCs from MM bone disease patients. The production of DcR3 by T lymphocytes confers these cells a role in the pathogenesis of bone disease associated with MM.
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PMID:Soluble decoy receptor 3 modulates the survival and formation of osteoclasts from multiple myeloma bone disease patients. 1958 6

RANKL is a key mediator of osteoclast differentiation, activation, and survival. Preclinical data suggest that aberrant production and activation of osteoclasts may influence proliferation of multiple myeloma (MM) cells in the bone marrow. Reports have also shown that inhibiting RANKL may have a direct effect on RANK-expressing myeloma cells and a therapeutic role in treating the disease. In mouse myeloma models, inhibition of RANKL led to reduced serum paraprotein levels and tumor burden. Based on this hypothesis, this proof-of-concept, single-arm study investigated whether RANKL inhibition with denosumab could reduce serum M-protein levels in relapsed or plateau-phase myeloma subjects. All subjects received denosumab monthly, with loading doses on days 8 and 15 of month one, until disease progression or subject discontinuation. Results of this ongoing study demonstrated that no subjects in either cohort met the protocol-defined objective response criteria of complete response (CR) or partial response (PR), but that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates, as evidenced by suppressed levels of the bone turnover marker, serum C-terminal telopeptide of type 1 collagen (sCTx). Eleven (21%) subjects who relapsed within 3 months before study entry maintained stable disease for up to 16.5 months. Nineteen (46%) subjects with plateau-phase myeloma maintained stable disease for up to 18.3 months. The adverse event (AE) profile for denosumab and its dosing schedule in these populations was consistent with that for advanced cancer patients receiving systemic therapy. Additional controlled clinical studies of denosumab in subjects with both relapsed and plateau-phase MM are warranted.
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PMID:An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma. 1971 3

Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) receptor superfamily, contributes determinatively to the bone remodeling as well as to the pathogenetic mechanism of bone malignancies and disorders of mineral metabolism. There is additional evidence that OPG can promote cell survival by inhibiting TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. A number of recent in vitro, in vivo and clinical studies have defined the role of the RANK/RANKL/OPG pathway in skeletal and vascular diseases. These works were the milestone of the deep understanding of the mechanism of OPG. This review provides an overview of the potential innovative therapeutic strategies of OPG in metastatic breast and prostate carcinoma, multiple myeloma, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis and rheumatoid arthritis. Special reference is given to the increasing evidence that RANKL and OPG may link the skeletal with the vascular system.
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PMID:Therapeutic implications of osteoprotegerin. 1974 96

Cancer and its treatment can compromise bone health, leading to fracture, pain, loss of mobility, and hypercalcemia of malignancy. Bone metastasis occurs frequently in advanced prostate and breast cancers, and bony manifestations are commonplace in multiple myeloma. Osteoporosis and osteopenia may be consequences of androgen-deprivation therapy for prostate cancer, aromatase inhibition for breast cancer, or chemotherapy-induced ovarian failure. Osteoporotic bone loss and bone metastasis ultimately share a pathophysiologic pathway that stimulates bone resorption by increasing the formation and activity of osteoclasts. Important mediators of pathologic bone metabolism include substances produced by osteoblasts, such as RANKL, the receptor activator of nuclear factor kappa B ligand, which spurs osteoclast differentiation from myeloid cells. Available therapies are targeted to various steps in cascade of bone metastasis.
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PMID:The science and practice of bone health in oncology: managing bone loss and metastasis in patients with solid tumors. 1987 35

Bone disease (BD) is the hall-mark clinical feature of multiple myeloma (MM), accounting up to 60% of patients with bone pain at diagnosis and 60% with a pathologic fracture during the course of their disease. Experimental models, which recapitulate in vivo the human bone marrow microenvironment (HBMM) in immunodeficient mice have been recently developed as valuable tool for the study of MM pathophysiology as well as the experimental treatment of BD. At present, bisphosphonates are the mainstay treatment of MM-related BD. The growing information on the cellular and molecular bases of BD as well as the availability of novel anti-resorptive agents, such as the IgG1-anti-RANKL (AMG 161) Denosumab, are now depicting a new scenario where the treatment will be afforded by the use of different agents. Furthermore the availability of highthroughput molecular profiling approaches, including DNA microarrays and proteomics, is likely to provide new platforms for patients stratification and treatment individualization on specific targets. It is now the right time for a therapeutical approach which is rationally based on the complexity of the biopathology of MM-related BD.
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PMID:Challenging the current approaches to multiple myeloma-related bone disease: from bisphosphonates to target therapy. 2002 73


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