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)

The receptor activator of nuclear factor-kappaB ligand (RANKL), its cognate receptor RANK, and its natural decoy receptor osteoprotegerin have been identified as the final effector molecules of osteoclastic bone resorption. This has provided an ideal target for therapeutic interventions in metabolic bone disease. As described in previous reviews in this supplement, RANKL signaling is required for osteoclast differentiation, activation, and survival. Furthermore, in vivo inhibition of RANKL leads to immediate osteoclast apoptosis, and there are no in vivo models of bone resorption that are refractory to RANKL inhibition. Thus, the only step remaining in the development of a clinical intervention is the generation of a safe, effective, and specific drug that can inhibit RANKL in humans. Here we review the clinical development of denosumab (formerly known as AMG 162), which is a fully human mAb directed against RANKL. This discussion includes the breadth of 21 human studies that have led to the current phase 3 clinical trials seeking approval for use of this agent to treat postmenopausal women with low bone mineral density (osteoporosis) and patients with metastatic lytic bone lesions (multiple myeloma, and prostate and breast cancer).
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PMID:Clinical development of anti-RANKL therapy. 1763 46

We describe a new model of myeloma bone disease in which beta2m NOD/SCID mice injected with KMS-12-BM cells develop medullary disease after tail vein administration. Micro-computed tomography analysis demonstrated significant bone loss in the tibiae and vertebrae of diseased animals compared to controls, with loss of cortical bone (P<0.01), as well as trabecular bone volume, thickness and number (P<0.05 for all). Bone marrow of diseased animals demonstrated an increase in osteoclasts (P<0.01) and reduction in osteoblasts (P<0.01) compared to control animals. Both bone loss and osteoclast increase correlated with the degree of disease involvement. Mesenchymal stem cells (MSCs) were lentivirally transduced to express human osteoprotegerin (hOPG). Systemic administration of OPG expressing MSC reduced osteoclast activation (P<0.01) and trabecular bone loss in the vertebrae (P<0.05) and tibiae of diseased animals, to levels comparable to non-diseased controls. Because of its predominantly medullary involvement and quantifiable parameters of bone disease, the KMS-12-BM xenogeneic model provides unique opportunities to test therapies targeted at the bone marrow microenvironment.
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PMID:A new xenograft model of myeloma bone disease demonstrating the efficacy of human mesenchymal stem cells expressing osteoprotegerin by lentiviral gene transfer. 1787 22

Multiple myeloma is characterized by extensive bone destruction with little or no new bone formation. A multiplicity of factors including receptor activator NF-kappaB (RANKL), macrophage inflammatory protein-1alpha, interleukin-3 and interleukin-6 can induce osteoclast formation in myeloma and drive the bone destructive process. Furthermore, factors are also produced either in the microenvironment or by myeloma cells themselves, which inhibit osteoblast differentiation and new bone formation. The combination of increased osteoclast formation with little or no bone repair in response to the previous bone destruction explains the severity of the bone disease in myeloma. Studies of the pathophysiology of myeloma bone disease have identified several novel therapeutic targets. These include antibodies to RANKL, chemokine receptor antagonists, which block the effects of chemokines on osteoclast differentiation and proteasome antagonists, which can affect both RANKL production and osteoprotegerin levels as well as inhibit osteoclast and enhance osteoblast differentiation. In addition, many of the new biologic agents being used for the treatment of patients with myeloma also further inhibit the bone destructive process. New therapies that can target both the tumor as well as the severe bone disease should be on the horizon to treat this devastating complication of myeloma.
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PMID:Treatment strategies for bone disease. 1768 18

Osteoprotegerin (OPG) binds the ligand for receptor activator of nuclear factor kappaB (RANKL) to prevent association with its receptor RANK and inhibit osteoclast-mediated bone resorption. OPG has been reported, recently, to inhibit tumor necrosis factor-related apoptosis-induced ligand (TRAIL)-induced tumor cell apoptosis. This raises the possibility that OPG may play a unique role in regulating these two signaling pathways. However, there are little data on the interactions between OPG, RANKL, and TRAIL, and the relative affinity of OPG for these two ligands is unknown. In the present study we examined the ability of OPG to bind native human TRAIL and RANKL under physiological conditions. Native TRAIL was expressed in Escherichia coli, purified to homogeneity, and shown to induce human myeloma cell apoptosis. OPG inhibited native TRAIL from binding the TRAILR1 at 37 degrees C in vitro. Similarly, OPG prevented RANKL from binding to RANK. TRAIL also prevented OPG-mediated inhibition of RANKL from binding RANK. The affinity of OPG for native TRAIL and RANKL at 37 degrees C was determined by plasmon surface resonance analysis. OPG had a binding affinity for TRAIL of 45 nM, whereas the affinity of OPG for RANKL was 23 nM. These data suggest that OPG can bind both RANKL and TRAIL and that the affinity of OPG for these two ligands is of a similar order of magnitude. Furthermore, OPG prevented TRAIL-mediated reductions in cell viability, whereas TRAIL inhibited OPG-mediated inhibition of osteoclastogenesis in vitro. This highlights the pivotal role of OPG in regulating the biology of both RANKL and TRAIL.
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PMID:Investigating the interaction between osteoprotegerin and receptor activator of NF-kappaB or tumor necrosis factor-related apoptosis-inducing ligand: evidence for a pivotal role for osteoprotegerin in regulating two distinct pathways. 1770 40

Osteoprotegerin (OPG) acts as a decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG regulates bone remodeling and the immune response. The primary objective was to decipher, among human peripheral blood mononuclear leukocytes (PBML) that produce OPG, the subset(s) responsible for this synthesis and its regulation. To this end, normal human PBML and CD4-, 8-, 19-, 14-enriched subpopulations were studied in vitro for OPG synthesis. PBML were subjected to adherence and immunomagnetic separation, and OPG expression was analyzed by PCR, northern and western blotting, and ELISA. The antiapoptotic effects of OPG were studied on TRAIL-stimulated RPMI 8226 myeloma cells. OPG was time-dependently produced by primary CD4+ T lymphocytes exclusively. OPG secretion was upregulated by anti-CD3 antibody stimulation or incubation with interleukin (IL)-4, IL-1beta, TNF-alpha, GM-CSF, and vitamin D(3). In contrast, IL-10 inhibited the basal and IL-4-induced production of OPG by T cells. Conditioned media from activated T lymphocytes decreased TRAIL-induced apoptosis of RPMI 8226 cells. This effect was reversed by addition of RANKL to the T-cell conditioned media. As human immunodeficiency virus-1 (HIV-1) targets CD4+ T cells, we evaluated the effects of recombinant HIV-1 gp120 proteins on OPG synthesis. The gp120 from three different HIV-1 strains significantly reduced the basal output of OPG from T cells. Furthermore, all four protease inhibitors (PIs) used in highly active antiretroviral therapy decreased OPG synthesis by human blood T cells, nelfinavir being the most efficient PI. The simultaneous presence of an HIV-1 gp120 and a PI abrogated the basal output of OPG. In conclusion, these results highlight a new role for T lymphocytes involved in pathologies. Activated CD4+ T cells could, through OPG release, have a paracrine effect on adjacent cells and contribute to reduce the local process of bone remodeling and cellular apoptosis.
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PMID:Normal human primary CD4+ T lymphocytes synthesize and release functional osteoprotegerin in vitro. 1804 Feb 68

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.
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PMID:Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. 1805 40

Multiple myeloma (MM) is a B cell malignancy characterized by enhanced bone loss that commonly associated with diffuse osteopenia, focal lytic lesions, pathologic fractures, and bone pain. The key mechanism of bone damage in myeloma is the abnormal regulation in bone metastasis, with increased osteoclast function and decreased osteoblast activity. This article reviewed the factors implicated, such as receptor activator of nuclear factor-kappaB (RANK), receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1alpha (MIP-1alpha), SDF-1 and Wnt pathway. Further understanding of the regulation system of bone homeostasis helps to offer possible targets for future therapy.
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PMID:[Research on mechanism underlying bone damage in myeloma--review]. 1808 97

Osteoporosis represents a major healthcare burden, affecting approximately 10 million people aged over 50 years in the United States and with another 30 million or more at risk. One of the major contributing factors to osteoporosis is withdrawal of estrogen during menopause in women. Human and animal experiments have implicated pro-inflammatory cytokines as primary mediators of the accelerated bone loss at menopause including interleukin-1, tumor necrosis factor-alpha, and interleukin-6. Increased production of pro-inflammatory cytokines is associated with osteoclastic bone resorption in a number of disease states including rheumatoid arthritis, periodontitis, and multiple myeloma; estrogen withdrawal is associated with increased production of pro-inflammatory cytokines, and exposure of bone cultures to supernatants from activated leukocytes is associated with increased bone resorption. A major advance has been the discovery of RANKL, its receptor RANK, and the endogenous inhibitor osteoprotegerin. The binding of RANKL to RANK is essential for the differentiation and activation of osteoclasts and mediates the actions of essentially all known stimulators of osteoclastic bone resorption. RANKL expression is heightened in post- compared with pre-menopausal women, and this effect is attenuated by estrogen replacement therapy. RANKL is also a therapeutic target; a human antibody with high specificity and affinity to RANKL is currently under clinical evaluation for the treatment of osteoporosis in post-menopausal women and of metastatic bone disease in cancer patients with bone metastasis. Early data are promising.
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PMID:Osteoporosis and inflammation. 1824 May 39

Receptor activator of nuclear factor-kB (RANK), its ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) together play a key role in osteoclastogenesis. Alterations in the RANKL/ OPG ratio are central in the pathogenesis of bone loss, from osteoporosis in all its forms to malignancy-induced bone loss. This fact has led to the search for drugs capable of targeted RANKL inhibition in the management of skeletal disorders associated with bone loss. Promising preclinical data using OPG have paved the way for the development of the new agent denosumab, a high-affinity, high-specificity, fully human monoclonal antibody to RANKL, shown to be able to induce a dose-dependent, rapid, profound and sustained inhibition of bone resorption lasting for months after a single subcutaneous injection in healthy postmenopausal women, men and patients with multiple myeloma or metastatic breast cancer. Data from a phase II study in postmenopausal women with low bone mineral density (BMD) demonstrate that the sustained inhibition of bone resorption induced by three or six monthly subcutaneously administered denosumab was associated with significant increases in BMD for up to two years of treatment. Antifracture efficacy and long-term skeletal and extraskeletal safety of denosumab are being addressed in ongoing phase III trials. The potential of denosumab to prevent bone loss has also been demonstrated in malignancy-induced bone loss. Ongoing studies in rheumatoid arthritis are also promising.
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PMID:Denosumab: RANKL inhibition in the management of bone loss. 1830

Multiple myeloma (MM) is characterized by osteolytic bone lesions (OBL) that arise as a consequence of osteoblast inactivation and osteoclast activation adjacent to tumor foci within bone. Wnt signaling in osteoblasts regulates osteoclastogenesis through the differential activation and inactivation of Receptor Activator of Nuclear factor Kappa B Ligand (RANKL) and osteoprotegerin (OPG), positive and negative regulators of osteoclast differentiation, respectively. We demonstrate here that MM cell-derived DKK1, a soluble inhibitor of canonical Wnt signaling, disrupted Wnt3a-regulated OPG and RANKL expression in osteoblasts. Confirmed in multiple independent assays, we show that pretreatment with rDKK1 completely abolished Wnt3a-induced OPG mRNA and protein production by mouse and human osteoblasts. In addition, we show that Wnt3a-induced OPG expression was diminished in osteoblasts cocultured with a DKK1-expressing MM cell line or primary MM cells. Finally, we show that bone marrow sera from 21 MM patients significantly suppressed Wnt3a-induced OPG expression and enhanced RANKL expression in osteoblasts in a DKK1-dependent manner. These results suggest that DKK1 may play a key role in the development of MM-associated OBL by directly interrupting Wnt-regulated differentiation of osteoblasts and indirectly increasing osteoclastogenesis via a DKK1-mediated increase in RANKL-to-OPG ratios.
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PMID:Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. 1857 32


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