Bortezomib Protects Osteoblasts from Glucocorticoid-Induced Damage, and Enhances Glucocorticoid-Induced Toxicity Against Osteoclasts and Myeloma Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3523-3523
Author(s):  
Kent Soe ◽  
Thomas L. Andersen ◽  
Katarzyna Kupisiewicz ◽  
Torben Plesner ◽  
Jean-Marie Delaisse
Keyword(s):  
Multiple Myeloma ◽  
Bone Repair ◽  
Plasma Cells ◽  
Bone Cells ◽  
Negative Impact ◽  
Bone Destruction ◽  
Myeloma Cells ◽  
The Impact ◽  
Human Osteoclasts

Abstract Introduction: Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow, and leads most often to bone destruction by osteoclasts and prevention of bone repair by osteoblasts. Bortezomib and glucocorticoids are both powerful anti-myeloma drugs that are used for killing malignant plasma cells in the patients. Furthermore bortezomib has direct anti-osteoclastic and pro-osteoblastic properties that may contribute to bone protection in multiple myeloma, while glucocorticoids have more ambiguous effects on these bone cells and are clearly anti-osteoblastic. Recent clinical trials based on the combination of bortezomib and glucocorticoids drew the attention on the very promising anti-myeloma efficiency of this combination. However, the bone cell response of this combination has not been tested. In order to address this question, we performed an in vitro study, and importantly adapted our in vitro model to mimic the pharmacokinetics of bortezomib and glucocorticoid in the patients. Methods: Myeloma cell lines, primary human osteoclasts and osteoblast-like cells (MC3T3) were pulse-treated or not with clinically relevant doses of bortezomib (12.5, 25 or 50 nM) for 3 hours. Subsequently, the cells were exposed during a 3-day culture to 1.6 μM prednisolone which approximately corresponds to a dose of 50 mg prednisolone in a patient. The impact of the treatment on the cells was determined by survival, activity and gene expression. Results: Bortezomib as a single treatment was very efficient in killing sensitive myeloma cells (OPM2) whereas the more resistant cells (U266) were more efficiently killed in combination with prednisolone. The release of TRAP from primary human osteoclasts, a marker of osteoclastic activation, was strongly inhibited by bortezomib treatment alone, but only in combination with prednisolone did it result in killing of osteoclasts. Survival of osteoblast like cells was uninfluenced by treatment with bortezomib alone. In contrast, as shown previously, prednisolone strongly reduced osteoblast survival. Most importantly however, a 3 hr pre-treatment with bortezomib protected the osteoblasts against the detrimental effects of glucocorticoids. Ongoing investigations by Q-PCR indicate that important markers of osteoblast maturation remain high if the osteoblasts were pre-treated with bortezomib prior to prednisolone exposure. Conclusion: Our study demonstrates in conditions relevant to treatment of myeloma patients, that combining bortezomib and glucocorticoids has a direct synergistic effect against myeloma cells and osteoclasts, and that bortezomib protects directly osteoblasts from the negative impact of glucocorticoids. Thus, the combination of bortezomib and glucocorticoids is not only a powerful treatment of multiple myeloma itself, but also shows promise for treating myeloma bone disease.

scholarly journals Ticagrelor Modulates Proliferation in Multiple Myeloma Via P1 and P2 Receptor-Mediated Mechanisms

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5694-5694
Author(s):  
Elan Meltzer ◽  
Aranzazu Mediero ◽  
Carl Whatling ◽  
Jeffrey S Berger ◽  
Bruce Cronstein
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Research Funding ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Bone Destruction ◽  
Extracellular Adenosine ◽  
Myeloma Cells ◽  
Platelet Releasate

Abstract Background:Multiple Myeloma (MM) is a hematologic malignancy involving uncontrolled proliferation of plasma cells and is particularly trophic to bone where it induces osteoclast-mediated bone destruction. Ticagrelor is a platelet inhibitor that blocks P2Y12 receptors and inhibits ENT1-mediated adenosine uptake, thereby increasing extracellular adenosine, which activates P1 receptors. Prior studies demonstrate that ticagrelor increases life span in a murine model of MM via its effect on extracellular adenosine. Prior studies also demonstrate an increase in proliferation, in vitro, and tumor growth, in vivo, of MM cells in the presence of platelet releasate. Ticagrelor blocks in vitro platelet-stimulated myeloma proliferation, suggesting a positive relationship and interaction between active platelets and multiple myeloma. We therefore determined whether the effect of ticagrelor on myeloma cells was mediated by extra-cellular adenosine or/and inhibition of platelet function. Methods:Human primary myeloma cells (KMS) were incubated with ticagrelor (10-9-10-4 M) in the presence of 5ng/ml IL-6 in the absence/presence of an A2AR antagonist (ZM241385 10-6M) and platelets (1:500 myeloma cell:platelets). In other experiments MM cells were incubated in the presence of platelet releasate, releasate from platelets treated with ticagrelor, or ticagrelor alone. Proliferation was assayed by Cell Titer MTS assay (Promega). Results: Ticagrelor inhibited MM cell proliferation by 20% (p<0.0001, IC50=0.5µM). This effect was abrogated by ZM241385 (48±6% increased vs. ticagrelor, p<0.0001). Platelet releasate increased MM proliferation by 33±6% (p<0.05) and ticagrelor inhibited the effect of platelet releasate on MM cell proliferation (IC50=0.12µM). Conclusions:These results suggest that ticagrelor inhibits proliferation of malignant plasma cells by a mechanism dependent on both adenosine A2A and platelet P2Y12 receptors. Moreover, platelet releasate intensifies proliferation, and this effect is reversed when the P2Y12 receptor is blocked by ticagrelor. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Meltzer: NIH: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding. Mediero:AstraZeneca: Research Funding; Celgene: Research Funding; NIH: Research Funding. Whatling:AstraZeneca: Employment. Berger:Merck: Membership on an entity's Board of Directors or advisory committees; AZ: Research Funding. Cronstein:AstraZeneca: Consultancy, Research Funding; CanFite: Equity Ownership; Gizmo Therapeutics: Consultancy; Eli Lilly & Co.: Consultancy; NIH: Research Funding; Celgene: Research Funding.

scholarly journals Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽  
2021 ◽  
Author(s):  
Yinyin Xu ◽  
Jing Guo ◽  
Jing Liu ◽  
Ying Xie ◽  
Xin Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combined Treatment ◽  
Hypoxia Inducible Factor ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Downstream Target ◽  
Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

scholarly journals Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2195-2202 ◽  
Author(s):  
Masahiro Abe ◽  
Kenji Hiura ◽  
Javier Wilde ◽  
Keiji Moriyama ◽  
Toshihiro Hashimoto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Stromal Cells ◽  
Neutralizing Antibodies ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Myeloma Cells ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Abstract Multiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milieu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)–1α and MIP-1β, in MM cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1α and MIP-1β correlated well with the ability of myeloma cells to enhance osteoclastic bone resorption both in vitro and in vivo as well as in MM patients. In osteoclastogenic cultures of rabbit bone cells, cocultures with myeloma cells as well as addition of myeloma cell-conditioned media enhanced both formation of osteoclastlike cells and resorption pits to an extent comparable to the effect of recombinant MIP-1α and MIP-1β. Importantly, these effects were mostly reversed by neutralizing antibodies against MIP-1α and MIP-1β, or their cognate receptor, CCR5, suggesting critical roles of these chemokines. We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1α and MIP-1β induce expression of receptor activator of nuclear factor-κB (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1α and MIP-1β may be major osteoclast-activating factors produced by MM cells.

CD38-Targeted Immunochemotherapy Of Multiple Myeloma: Preclinical Evidence For Its Combinatorial Use In Lenalidomide and Bortezomib Refractory/Intolerant MM Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 277-277 ◽  
Author(s):  
Inger S. Nijhof ◽  
Willy A. Noort ◽  
Jeroen Lammerts van Bueren ◽  
Berris van Kessel ◽  
Joost M. Bakker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Plasma Cells ◽  
Cell Lysis ◽  
In Vitro Assays ◽  
Human Antibody ◽  
Myeloma Cells ◽  
Clinical Phase

Abstract Multiple myeloma (MM) remains an incurable malignancy of clonal plasma cells. Although the new generation of immunomodulatory agents, such as lenalidomide (LEN), and the potent proteasome inhibitor bortezomib (BORT) have significantly improved the overall survival of MM patients, all chemotherapy strategies are eventually hampered by the development of drug-resistance. The outcome of patients who are refractory to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor. Set out with the idea that targeted immunotherapy with human antibodies may offer new perspectives for MM patients, we have recently developed daratumumab (DARA), a CD38 human antibody with broad-spectrum killing activity, mainly via ADCC (antibody dependent cellular cytotoxicity) and CDC (complement dependent cytotoxicity). In our previous preclinical studies and in current clinical phase I/II trials, DARA induces marked anti-MM activity. Based on these encouraging results, we now explored the potential activity of DARA for patients who are refractory to LEN- and/or BORT. In a recently developed human-mouse hybrid model that allows the in vivo engraftment and outgrowth of patient-derived primary myeloma cells in immune deficient Rag2-/-gc-/- mice, single dose DARA treatment appeared to effectively inhibit the malignant expansion of primary MM cells derived from a LEN- and BORT-refractory patient, indicating the potential efficacy of DARA even in LEN/BORT refractory patients. To substantiate the conclusions of these in vivo data, we conducted in vitro assays, in which full BM-MNCs from LEN (n=11) and LEN/BORT (n=8) refractory patients were treated with DARA alone or the combination of DARA with LEN or BORT to induce MM cell lysis. As expected, LEN alone induced no or little lysis of MM cells in the LEN-refractory patients and also BORT was not able to induce any lysis in the BORT-refractory patients. On the contrary, DARA induced substantial levels of MM cell lysis in all LEN and LEN/BORT-refractory patients. This lysis was significantly enhanced by combination with LEN or BORT. The combination of DARA and BORT improved MM lysis by additive mechanisms. However, LEN improved DARA-mediated lysis of MM cells in a synergistic manner through the activation of effector cells involved in DARA-mediated ADCC. In conclusion, our results demonstrate that DARA is also effective against multiple myeloma cells derived from LEN- and BORT-refractory patients. Especially LEN seems to improve responses in a synergistic manner. Our results provide a rationale for clinical evaluation of DARA in combination with LEN to achieve more effective results in LEN- and BORT-refractory patients. Disclosures: Lammerts van Bueren: Genmab: Employment. Bakker:Genmab: Employment. Parren:Genmab: Employment. van de Donk:Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.

Mcl-1 Is Overexpressed in Multiple Myeloma and Correlates with Disease Severity.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1419-1419
Author(s):  
Soraya Wuilleme-Toumi ◽  
Nelly Robillard ◽  
Patricia Gomez-Bougie ◽  
Philippe Moreau ◽  
Steven Le Gouill ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Disease Severity ◽  
Cell Lines ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Lymphocytic Leukemia ◽  
Myeloma Cells

Abstract Multiple Myeloma (MM) is a fatal malignancy of B-cell origin characterized by the accumulation of plasma cells within the bone marrow. The expression of the pro-survival members of the Bcl-2 family has been shown to be a key process in the survival of myeloma cells. More particularly, Mcl-1 expression turned out to be critical for their survival. Indeed, knockdown of Mcl-1 by antisenses induces apoptosis in myeloma cells. Finally, Mcl-1 was found to be the only anti-apoptotic Bcl-2 family member which level of expression was modified by cytokine treatment of myeloma cells. For these reasons, we have evaluated the expression of Mcl-1 in vivo in normal, reactive and malignant plasma cells (PC) i.e., myeloma cells from 55 patients with MM and 20 human myeloma cell lines using flow cytometry. We show that Mcl-1 is overexpressed in MM in comparison with normal bone marrow PC. Forty-seven percent of patients with MM at diagnosis (p=.017) and 80% at relapse (p=.014 for comparison with diagnosis) overexpress Mcl-1. Of note, only myeloma cell lines but not reactive plasmocytoses have abnormal Mcl-1 expression, although both plasmocyte expansion entities share similar high proliferation rates (&gt;20%). Of interest, Bcl-2 as opposed to Mcl-1, does not discriminate malignant from normal PC. This shows that the overexpression of Mcl-1 is clearly related to malignancy rather than to proliferation. It will be important to know whether the overexpression of Mcl-1 is related to an abnormal response to cytokines like Interleukin-6 or to mutations of the promoter of the Mcl-1 gene as already described in B chronic lymphocytic leukemia. Finally, level of Mcl-1 expression is related to disease severity, the highest values being correlated with the shortest event-free survival (p=.01). In conclusion, Mcl-1 which has been shown to be essential for the survival of human myeloma cells in vitro is overexpressed in vivo in MM and correlates with disease severity. Mcl-1 represents a major therapeutical target in MM.

Targeting the CD28-B7 Pro-Survival Pathway In Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 132-132 ◽  
Author(s):  
Jayakumar Nair ◽  
Louise Carlson ◽  
Cheryl H Rozanski ◽  
Chandana Koorella ◽  
Megan Murray ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Kinase Activity ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Flow Cytometric Analysis ◽  
Myeloma Cell ◽  
Serum Starvation ◽  
Myeloma Cells ◽  
Survival Signals

Abstract Abstract 132 Multiple myeloma (MM), an incurable neoplasia of terminally differentiated plasma cells, are critically dependent on their interactions with bone marrow stromal cells (BMSC) for essential survival signals, growth and immunosuppressive factors. Very little is known about the specific BM cell type or the molecular elements in these interactions, an understanding of which could provide novel targets that could be interdicted to enhance conventional chemotherapy. A potential MM surface protein that could be involved in these interactions is CD28, based on its known pro-survival role in T cells. Clinical studies have shown that expression of CD28 in multiple myeloma highly correlates (p=0.006) with myeloma tumoral expansion. Moreover, CD28+ MM cells invariably express the CD28 ligand CD86. A survival role for MM-CD28 might involve interactions with BM cells that express B7 (CD80/CD86) such as dendritic cells (DCs, that are known to be closely associated with MM cells in the BM) or with CD86+ MM cells themselves. We had previously shown (ASH2008, #I-769) that blocking CD28-CD86 interactions between myeloma cells with high affinity B7 ligand CTLA4Ig (Abatacept®) sensitized myeloma cells to chemotherapy. Now we show that myeloma cells co-cultured with myeloid DCs in vitro derive both direct and indirect survival signals from DCs, and this can be partially blocked by commercially available reagents. Our data show that flow cytometric analysis of mononuclear cells (MNC) from BM aspirates of myeloma patients with increased CD138+ plasma cell populations (9-58%), show an increased CD11b+ (myeloid) population (20-37%) as well, which is in contrast to healthy transplant donor controls (12-15% CD11b+, 4–6% CD138+). Moreover, a larger fraction (11-47%) of the myeloma CD138+ plasma cells expressed CD28 compared to healthy control (3.3-7.7%). Also, when we analyzed gene expression datasets (NCBI #GSE5900 and GSE4204) from plasma cells (PC) of normal donors, monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SM) and newly diagnosed multiple myeloma (MM), we found a progressive increase in patients showing CD28 expression with increasing severity of disease (normal<MGUS<SM<MM) (Fig 1A). When we sorted the highest scoring MM group (n=538) into 8 genetic subgroups as defined earlier, CD28 expression was found to peak in the MF subgroup (typically associated with poor survival in myeloma patients) (Zhan et al. 2006, Blood 108, pp. 2020) relative to total population (p<0.0001) (Fig 1B). Antibody mediated activation of MM-CD28 over 48 hrs increased viability of myeloma cell line MM.1S cultured under serum starvation (3.7%) or with drugs ATO (1.9%), melphalan (18%) or dexamethasone (3.3%) to 66%, 21%, 33% and 11% respectively. Viability of MM.1S cells or primary CD138+ plasma cells (isolated from myeloma BM aspirates) cultured under serum starvation was enhanced >3 fold (p<0.001) when co-cultured with monocyte derived DCs, and in MM.1S this was partially reversed when either MM-CD28 or DC-B7 was blocked (Fig 2). Similar protection of MM.1S was also observed against a gradient of dexamethasone or melphalan. CD28 activation was accompanied by rapid tyrosine phosphorylation of CD28, association of p85 (PI3K), activation of Vav-1 and increase in CD28 associated tyrosine kinase activity, as shown by immunoprecipitation, western and kinase activity assays. We had previously shown that MM-CD28 interaction drive DC production of pro-survival factor IL-6 and immunosuppressive factor IDO via DC-B7 “backsignaling” (ASH2008 #I-769). Now we show that MM induced DC production of IL-6 (8 ng/ml) was partially inhibited in presence of CD28 blocking αCD28(Fab) fragments (3 ng/ml) or with protein kinase C (PKC) inhibitor Bisindolylmaleimide-I (2.1ng/ml). Activity of the immunosuppressive enzyme IDO in these co-cultures was completely inhibited in the presence of a novel IDO inhibitor from Incyte corporation, and this helped partially reverse IDO mediated suppression of T-cell proliferation in proliferation assays using co-culture supernatants. In conclusion, our data characterizes CD28-B7 pathway and DCs in the BM as vital for myeloma survival and also as possible targets to include in future strategies in the treatment of myeloma. FIGURE 1 FIGURE 1. FIGURE 2 FIGURE 2. Disclosures: Boise: University of Chicago: Patents & Royalties.

A unique three-dimensional model for evaluating the impact of therapy on multiple myeloma

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2935-2945 ◽  
Author(s):  
Julia Kirshner ◽  
Kyle J. Thulien ◽  
Lorri D. Martin ◽  
Carina Debes Marun ◽  
Tony Reiman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Three Dimensional ◽  
Preclinical Model ◽  
Drug Resistant ◽  
Three Dimensional Model ◽  
The Impact

AbstractAlthough the in vitro expansion of the multiple myeloma (MM) clone has been unsuccessful, in a novel three-dimensional (3-D) culture model of reconstructed bone marrow (BM, n = 48) and mobilized blood autografts (n = 14) presented here, the entire MM clone proliferates and undergoes up to 17-fold expansion of malignant cells harboring the clonotypic IgH VDJ and characteristic chromosomal rearrangements. In this system, MM clone expands in a reconstructed microenvironment that is ideally suited for testing specificity of anti-MM therapeutics. In the 3-D model, melphalan and bortezomib had distinct targets, with melphalan targeting the hematopoietic, but not stromal com-partment. Bortezomib targeted only CD138+CD56+ MM plasma cells. The localization of nonproliferating cells to the reconstructed endosteum, in contact with N-cadherin–positive stroma, suggested the presence of MM-cancer stem cells. These drug-resistant CD20+ cells were enriched more than 10-fold by melphalan treatment, exhibited self-renewal, and generated clonotypic B and plasma cell progeny in colony forming unit assays. This is the first molecularly verified demonstration of proliferation in vitro by ex vivo MM cells. The 3-D culture provides a novel biologically relevant preclinical model for evaluating therapeutic vulnerabilities of all compartments of the MM clone, including presumptive drug-resistant MM stem cells.

scholarly journals Phagocytic plasma cells in a patient with multiple myeloma

Blood ◽  
1980 ◽  
Vol 56 (2) ◽  
pp. 173-176 ◽  
Author(s):  
H Ludwig ◽  
M Pavelka
Keyword(s):  
Multiple Myeloma ◽  
Female Patient ◽  
Phagocytic Activity ◽  
Plasma Cells ◽  
Red Cells ◽  
Microscopical Investigation ◽  
Myeloma Cells ◽  
Latex Particles ◽  
Electron Microscopical

Abstract A female patient with IgG multiple myeloma and phagocytosing plasma cells is presented. Electron microscopical investigation showed an unusually large number of small mitochondria in the myeloma cells. In 21%, intracytoplasmic incorporation of one or more red cells or occasionally of erythroblasts or cells of the myeloid series were found. Uptake of platelets was seen rarely only. Studies of the in vitro phagocytic activity of myeloma cells did not reveal phagocytosis of opsonized bacteria or of latex particles by the malignant plasma cells.

Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 3002-3007 ◽  
Author(s):  
Therese Standal ◽  
Carina Seidel ◽  
Øyvind Hjertner ◽  
Torben Plesner ◽  
Ralph D. Sanderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Bone Destruction ◽  
Nuclear Factor Κb ◽  
Heparin Binding ◽  
Bone Homeostasis ◽  
Myeloma Cells ◽  
Heparan Sulfates

Multiple myeloma (MM) is a hematologic malignancy characterized by accumulation of plasma cells in the bone marrow (BM). Bone destruction is a complication of the disease and is usually associated with severe morbidity. The balance between receptor activator of nuclear factor-κB (NF-κB) ligand and osteoprotegerin (OPG) is of major importance in bone homeostasis. We have recently shown that serum OPG levels are lower in patients with myeloma than in healthy individuals. Here we show that myeloma cells can bind, internalize, and degrade OPG, thereby providing a possible explanation for the lower levels of OPG in the BM of patients with MM. This process is dependent on interaction of OPG with heparan sulfates on the myeloma cells. The results suggest a novel biologic mechanism for the bone disease associated with MM and that treatment of the bone disease with OPG lacking the heparin-binding domain should be considered.

scholarly journals Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2195-2202 ◽  
Author(s):  
Masahiro Abe ◽  
Kenji Hiura ◽  
Javier Wilde ◽  
Keiji Moriyama ◽  
Toshihiro Hashimoto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Stromal Cells ◽  
Neutralizing Antibodies ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Myeloma Cells ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Multiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milieu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)–1α and MIP-1β, in MM cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1α and MIP-1β correlated well with the ability of myeloma cells to enhance osteoclastic bone resorption both in vitro and in vivo as well as in MM patients. In osteoclastogenic cultures of rabbit bone cells, cocultures with myeloma cells as well as addition of myeloma cell-conditioned media enhanced both formation of osteoclastlike cells and resorption pits to an extent comparable to the effect of recombinant MIP-1α and MIP-1β. Importantly, these effects were mostly reversed by neutralizing antibodies against MIP-1α and MIP-1β, or their cognate receptor, CCR5, suggesting critical roles of these chemokines. We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1α and MIP-1β induce expression of receptor activator of nuclear factor-κB (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1α and MIP-1β may be major osteoclast-activating factors produced by MM cells.

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