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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 671-675
NEOPLASIA
Macrophage inflammatory protein 1-alpha is a potential osteoclast
stimulatory factor in multiple myeloma
Sun Jin Choi,
Jose C. Cruz,
Fiona Craig,
Hoyeon Chung,
Rowena D. Devlin,
G. David Roodman, and
Melissa Alsina
From the Departments of Medicine/Hematology and Pathology,
University of Texas Health Science Center, San Antonio, TX; Cheil
General Hospital, Seoul, Korea; St. Francis Hospital and Medical
Center, Hartford, CT; and the General Clinical Research Center and
Research Service of the Audie L. Murphy Veterans Administration
Hospital, San Antonio, TX.
 |
Abstract |
This study was designed to determine if macrophage inhibitory
protein-1 (MIP-1), a recently described osteoclast (OCL)
stimulatory factor,1 was present in marrow
from patients with multiple myeloma (MM) and possibly involved in the
bone destructive process. MIP-1, but not interleukin-1 (IL-1),
tumor necrosis factor- (TNF-), or interleukin-6 (IL-6), messenger
RNA was elevated in freshly isolated bone marrow from 3 of 4 patients
with MM compared to normal controls. Furthermore, enzyme-linked
immunosorbent assays of freshly isolated bone marrow plasma detected
increased concentrations of hMIP-1 (range, 75-7784 pg/mL) in 8 of 13 patients (62%) with active myeloma, in 3 of 18 patients (17%) with
stable myeloma (range, 75-190.3), as well as in conditioned media from
4 of 5 lymphoblastoid cell lines (LCLs) derived from patients with MM. Mildly elevated levels of MIP-1 were detected in 3 of 14 patients (21%) with other hematologic diagnoses (range, 80.2-118.3, median value of 96 pg/mL) but not in normal controls (0 of 7). MIP-1 was
not detected in the peripheral blood of any patients with MM. In
addition, recombinant hMIP-1 induced OCL formation in human
bone marrow cultures. Importantly, addition of a
neutralizing antibody to MIP-1 to human bone marrow cultures treated
with freshly isolated marrow plasma from patients with MM blocked
the increased OCL formation induced by these marrow samples but
had no effect on control levels of OCL formation. Thus,
high levels of MIP-1 are expressed in marrow samples from patients
with MM, but not in marrow from patients with other hematologic
disorders or controls, and support an important role for MIP-1 as
one of the major factors responsible for the increased OCL
stimulatory activity in patients with active MM.
(Blood. 2000;96:671-675)
© 2000 by The American Society of Hematology.
| |
Introduction |
Multiple myeloma (MM) is an incurable plasma cell
neoplasm that accounts for 13% of hematologic
malignancies.1 Bone destruction is a common manifestation
of the disease and is a major source of morbidity for these patients.
Bone destruction results from increased osteoclastic bone resorption
and decreased bone formation that occur only in areas of bone adjacent
to myeloma cells.2,3 These data suggest that the bone
disease results from local production of an osteoclast stimulatory
factor (OSF) that is secreted by myeloma cells, marrow stromal cells,
or both. The identity of this factor(s) in vivo is currently unknown.
In vitro studies have implicated several cytokines as responsible for
bone destruction in myeloma,4 including interleukin-1 (IL-1),5,6 interleukin-6 (IL-6),7 and
lymphotoxin.8 Nevertheless, none of these cytokines has
been found to be elevated consistently in the peripheral blood of
patients with MM.9 Failure to detect these factors may
reflect the possibility that they are only secreted locally in areas of
the bone marrow that contain increased numbers of malignant plasma
cells. Alternatively, other factors may be responsible for the bone
destruction in patients with MM.
To try to identify the OSF present in patients with MM, we tested
freshly isolated bone marrow plasma from heparinized marrow aspirates
from patients with MM for their capacity to induce osteoclast (OCL)
formation in human marrow cultures and have further characterized this
activity. Our results show that bone marrow plasma from patients with
MM significantly stimulated OCL formation in human bone marrow cultures
when compared to normal controls. This OSF differed from the
bone-resorbing cytokines previously implicated in myeloma bone disease.
These data suggested that a different factor may be responsible for the
bone destruction in patients with MM. Therefore, we determined if the
chemokine macrophage inflammatory protein-1 (MIP-1) was present
in marrow samples from patients with MM.
Macrophage inflammatory protein-1 is a low molecular weight
chemokine that can stimulate phagocyte activity,10 induce
OCL formation in rat marrow cultures,11 and is chemotactic
for OCLs.12 MIP-1 belongs to the RANTES family of
chemokines in which the first 2 cysteine residues of a conserved 4 cysteine motif are not separated by an intervening amino acid (C-C).
These chemokines act as chemoattractants and activators of monocytes.
MIP-1 inhibits hematopoiesis by inhibiting the proliferation of
CD34+ cells and has been implicated in the pathogenesis
of anemia in patients with MM.13 In the current study we
show that MIP-1 is an OCL-stimulating factor in human marrow
cultures and that it is overexpressed in patients with MM but not in
controls. More important, a neutralizing antibody to MIP-1 blocks
the OSF activity present in bone marrow plasma from MM patients. These
data suggest MIP-1 may be a major mediator of the bone destruction
seen in patients with MM.
| |
Materials and methods |
Bone marrow samples
Bone marrow aspirates were collected into heparinized syringes from
patients with MM (Durie-Salmon, stages I-III), normal controls, and
patients with a variety of hematologic diseases involving the marrow.
All patients gave informed consent, and these studies were approved by
the Institutional Review Board of the University of Texas Health
Science Center at San Antonio. Bone marrow (10 mL) was collected in a
single aspiration from each subject, and an aliquot of the bone marrow
sample was stained with Wright-Giemsa for histologic examination. The
percentage of plasma cells present in the sample was determined by
morphologic criteria. The bone marrow was pelleted by centrifugation at
1000 × g at 4°C immediately after collection, and
the bone marrow plasma was collected and stored at  80°C for
subsequent studies. The cells were resuspended in -Minimal Essential
Media (MEM)/5% fetal calf serum (FCS), and the mononuclear cell
fraction separated by gradient centrifugation.14
Mononuclear cells were resuspended at 1 mL/5 × 106
cells and RNA was extracted from the cells using RNAzol according to
the manufacturer's protocol (Biotecx Laboratories, Houston, TX).
Peripheral blood plasma samples from the patients were collected at the
time of bone marrow examination.
Cell lines
Lymphoblastoid cell lines (LCLs) derived from patients with MM
including IM9,15 RPMI-8226,16
MCCAR,17 SKO,18 and ARH-7719 were
grown in RPMI 1640 media containing 10% FCS (Gibco, Grand Island, NY)
for 5 days. Initially, 5 × 106 cells were plated.
The IM9, MCCAR, and ARH-77 cell lines are Epstein-Barr virus
(EBV)-transformed cells. After 5 days of culture, conditioned media
were collected and saved in aliquots at 80°C for
enzyme-linked immunosorbent assays (ELISA).
Osteoclast formation assays
Nonadherent marrow mononuclear cells from normal donors were
prepared as previously described14 and resuspended in
MEM/20% horse serum (MEM, Gibco; horse serum, Hyclone, Logan,
UT) at 106 cells/mL in quadruplicate. The normal marrow
cells (1 × 105 cells/well) were plated in 96-well
plates and treated with varying concentrations of bone marrow plasma
from MM patients and controls or recombinant MIP-1. In selected
experiments, neutralizing antibodies to MIP-1, tumor necrosis factor
(TNF)-, IL-6, or IL-1 (anti-MIP-1 and TNF-: R & D,
Minneapolis, MN; anti-IL-6 and IL-1: Genzyme, Cambridge, MA) were
added to cultures treated with bone marrow plasma. Cultures were
maintained in a humidified atmosphere of 4% CO2 and air at
37°C for 3 weeks. The cultures were fed weekly by replacing half
the media with an equal volume of fresh media. Cells were fixed with
2% formaldehyde in phosphate-buffered saline (PBS), and the number of
OCL-like multinucleated cells scored with the 23c6 monoclonal antibody,
which identifies OCLs (generously provided by Dr Michael Horton, St.
Bartholomew's Hospital, London, UK).20 Binding of the 23c6
monoclonal antibody was assessed with biotin-conjugated rabbit
antimouse IgG coupled to alkaline phosphatase (Vector Laboratories,
Burlingame, CA). The cells were counterstained with methyl
green.21 We have previously demonstrated that
multinucleated cells that cross-react with the 23c6 monoclonal antibody
(23c6Ab+ multinucleated cells) express calcitonin
receptors, contract in response to calcitonin, and form resorption
lacunae on calcified matrices, all phenotypic characteristics of
OCLs.14,21-23 OCL-like cell formation in these cultures
ranged from 50 to 150 23c6+ multinucleated cells per
105 marrow cells plated, depending on the donor marrow used.
Messenger RNA analysis
Total RNA was analyzed by RNAse protection assay using probes
derived from the human MIP-1 messenger RNA (mRNA) sequence. Radiolabeled human MIP-1 antisense transcripts were synthesized from linearized DNA templates, using 32P-UTP (800 Ci/mole;
Amersham, Arlington Heights, IL) and the MIP-1-specific primers [5'
ACA TTC CGT CAC CTG TCA AG 3' (sense) and 5' CGG TCG TCA
CCA GAC GCG G 3' (antisense)]. RNAse protection assays were performed using the RPA III kit (Ambion Inc, Austin, TX) with human
reduced glyceraldehyde-phosphate dehydrogenase (GAPDH) as the internal
control. RNA (10 µg) from normal donors and patients with MM were
hybridized with 50 000 cpm of antisense RNA probe. After gel analysis
followed by autoradiography, protected bands were quantified by densitometry.
Measurement of IL-6, IL-1, lymphotoxin, and MIP-1 levels in
bone marrow plasma from patients with MM and controls
The concentrations of IL-6, IL-1, lymphotoxin, and MIP-1 in
the bone marrow plasma from patients with MM, normal controls, and
patients with other hematologic malignancies were determined using
specific ELISAs, following the manufacturers' protocols (IL-6 and
IL-1, Genzyme; lymphotoxin and MIP-1, R & D Systems). The
concentration of MIP-1 was also measured in media conditioned for 5 days by 5 human LCLs. These assays can detect as little as 20 pg/mL of
the respective cytokines. MIP-1 levels were considered significantly
elevated if they were 2 SD above the upper limit of MIP-1 detected
in bone marrow plasma from 7 normal individuals, that is,
42.49 + 2(15.9). Therefore, levels of MIP-1 greater than 75 pg/mL were considered to be significantly elevated.
Statistical analysis
Results are presented as the mean ± SEM. Differences between the
means were compared by a 1-way analysis of variance and considered significant for P less than .05.
| |
Results |
Effects of bone marrow plasma from patients with MM and controls on
OCL formation
Bone marrow plasma from 24 of 27 patients with MM tested
significantly stimulated the formation of OCLs in human bone marrow cultures when compared to controls (47.75 ± 6 [mean ± SEM
for the 24 patients] versus 28.25 ± 5 23c6+
multinucleated cells/105 cells plated [mean ± SEM]
for the 6 controls; P < .05) (Figure 1A). The relative levels of OCL formation
induced by marrow plasma from patients with MM with normal renal
function positively correlated with 2 microglobulin
levels (Figure 1B; correlation coefficient = 0.708).
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| Fig 1.
Stimulation of OCL formation.
(A) Effects of bone marrow plasma from controls and patients with MM on
OCL formation in human marrow cultures. Bone marrow plasma and marrow
cultures were processed as described in "Materials and methods."
Results represent the mean ± SEM for all assays done in
quadruplicate. Bone marrow plasma from patients with MM significantly
stimulated the formation of OCLs in human bone marrow cultures when
compared to controls (47.75 ± 6 versus 28.25 ± 5
multinucleated cells/105 cells plated, respectively,
P < .05). (B) Correlation of OCL formation induced by
marrow plasma from 12 patients with MM and their respective levels of
2 microglobulin. Bone marrow plasma and marrow cultures
were processed as described in "Materials and methods." The
relative levels of OSF positively correlated with 2
microglobulin levels in patients with MM with normal renal function
(correlation coefficient = 0.708).
|
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Measurement of cytokine levels
Levels of IL-6, IL-1, and lymphotoxin were measured using a
sensitive ELISA that could detect a minimum of 18 pg/mL, 20 pg/mL, and
16 pg/mL of the cytokines, respectively. None of the 24 patients with
MM or the 10 controls had detectable levels of IL-6, IL-1, or
lymphotoxin in their bone marrow plasma.
Levels of MIP-1 were then measured by ELISA in freshly isolated
bone marrow plasma from 31 patients with MM, 14 patients with other
hematologic diagnoses, 7 normal controls, and 5 LCLs. Two patients with
MM had stage I disease and 29 had stage III disease (Table
1). Disease activity was classified
according to standard response criteria as inactive if disease
parameters (2 microglobulin, level of monoclonal
protein, hemoglobin, Ca++ levels, and extent of bone
disease) were consistent with stable or responsive disease, or active
if patients were newly diagnosed or disease parameters were consistent
with progressive disease.
Overall, 11 of 31 patients with MM, 0 of 7 normal controls, and 3 of 14 patients with other hematologic disorders had increased levels of
MIP-1. A significantly larger proportion of MM patients with active
disease (8 of 13) had increased levels of MIP-1 (median value; 178.1 pg/mL) compared to patients with MM with inactive disease (3 of 18).
MIP-1 levels were more than 1500 pg/mL in the conditioned media from
4 of 5 of the LCLs tested.
Figure 2 shows the levels of MIP-1 in
the different groups examined. MIP-1 levels were significantly
higher in the patients with stage III MM with active disease
(732.5 ± 588.98 pg/mL) when compared to normal controls
(6.52 ± 6.01 pg/ml), patients with other hematologic diseases
(55.7 ± 9.98 pg/mL), stage I MM patients (29.78 ± 13.81
pg/mL), and patients with stage III MM and inactive disease
(40.58 ± 12.21 pg/mL) (P < .05). In the 3 patients
with increased MIP-1 levels and non-MM hematologic diseases, the
median MIP-1 level was 96.6 pg/mL.
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| Fig 2.
Comparison of levels of MIP-1 in marrow plasma from
controls and patients with different stages of MM
. MIP-1 levels were measured as described in "Materials and
methods." MIP-1 levels were significantly higher
(P < .05) in the patients with active disease compared to
patients with inactive disease, patients with stage I MM, or normal
controls. The dashed horizontal line represents the upper limit for
normals ± 2 SD (75 pg/mL). Levels above this value were considered
to be significantly elevated. The horizontal bars represent the mean
for each group. The vertical bars represent the SEM for each group.
Because the values in the y-axis are in logarithm scale, MIP-1
levels of 0 pg/mL in each group do not appear on the graph.
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|
Effects of MIP-1 on OCL formation in human bone marrow
cultures
MIP-1 significantly stimulated OCL formation in human bone marrow
cultures at concentrations of 100 to 200 pg/mL. The maximum effect was
seen at 200 pg/mL (Figure 3).
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| Fig 3.
Effects of recombinant human MIP-1 on OCL formation in
human marrow cultures
. Human marrow cultures were processed as described in "Materials
and methods." MIP1- significantly stimulated OCL formation in
human bone marrow cultures when tested at concentrations of 100 to 200 pg/mL. Results represent the mean ± SEM of quadruplicate
determinations for a typical experiment. A similar pattern of results
was seen in 4 independent experiments.
|
|
Expression of MIP-1 mRNA in bone marrow samples from patients
with MM
To compare the levels of expression of MIP-1 mRNA in patients
with stage III MM and normal donor bone marrow, we performed RNAse
protection assays for MIP-1 and GAPDH mRNA levels. MIP-1 mRNA
expression was increased approximately 2- to 8-fold in 3 of 4 patients
with stage III MM compared to the normal donors (P < .05)
(Figure 4).
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| Fig 4.
Reverse transcription-polymerase chain reaction (RT-PCR)
analysis of MIP-1 mRNA expression in patients with MM
. Cycle-dependent RT-PCR was performed for 16, 20, or 24 cycles (lanes
1, 2, and 3) as described in "Materials and methods." Results
represent the mean ± SEM for 3 determinations for each patient.
MIP-1 mRNA expression in patients with stage III MM was increased
approximately 2- to 5-fold compared to controls in 3 of 4 patients with
MM. A similar pattern of results was seen in 2 independent
experiments.
|
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Effects of a neutralizing antibody to MIP-1 on OCL formation
induced by bone marrow plasma from patients with MM
We tested the effects of anti-MIP-1, anti-IL-6, anti-IL-1,
and anti-TNF- on the OSF activity present in bone marrow plasma from patients with MM. Anti-MIP-1 at a concentration of 3 ng/mL, which can neutralize up to 10 ng/mL of MIP-1, blocked OCL formation in human bone marrow cultures treated with bone marrow plasma from 2 patients with MM (Figure 5).
Anti-MIP-1 had no effects on basal OCL formation in untreated
cultures. Anti-IL-6, anti-IL-1, and anti-TNF did not block OCL
formation induced by marrow plasma from patients with MM (data not
shown). Marrow plasma from normal controls did not stimulate OCL
formation (data not shown).
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| Fig 5.
Effects of anti-MIP-1 on OCL formation induced by
marrow plasma from patients with MM
. Marrow plasma and marrow cultures were processed as described.
Anti-MIP-1 at a concentration of 3 ng/mL, which neutralized up to 10 ng/mL of MIP-1, blocked the OCL formation induced by the bone marrow
plasma of 2 patients with MM in human bone marrow cultures. Results
represent the mean ± SEM for a typical experiment. A similar
pattern of results was seen in cultures from a total of 5 of 6 myeloma
marrow plasma samples.
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| |
Discussion |
Bone destruction commonly occurs in patients with MM and is mediated
by increased osteoclastic bone resorption and decreased bone formation
in areas of bone adjacent to myeloma cells.24 The factors
that mediate this abnormal bone remodeling in vivo are unknown. It is
likely that myeloma cells secrete factor(s) that induce OCL activation
either directly or indirectly, possibly through interactions with
marrow stromal cells.
Several cytokines, in particular IL-1,5,6
IL-6,7 and lymphotoxin,8 have been implicated
as OCL-stimulating factors in MM, based on in vitro studies, but in
vivo studies have failed to confirm a role for these cytokines in the
pathogenesis of myeloma bone disease. For example, IL-1 has been
proposed as the major OCL-activating factor in MM, but the results have
been controversial. Increased levels of IL-1 have been
detected in cultures of freshly isolated myeloma cells by
ELISA.25 Differential expression of IL-1 mRNA has been
detected by in situ hybridization in bone marrow samples from patients
with MM compared to samples from patients with monoclonal gammopathy of
unknown significance.26 In contrast, normal levels of
IL-1 have been reported in the plasma of patients with
MM.9 Similarly, in the current study, IL-6, IL-1, and
lymphotoxin were undetectable in freshly isolated bone marrow plasma
from 24 of 24 patients with stage III MM, using highly sensitive ELISA
assays, which could detect cytokine concentrations as low as 20 pg/mL.
Furthermore, although IL-1 was the only bone-resorbing cytokine
detected in the bone marrow plasma obtained from our recently described
in vivo model of myeloma bone disease,27 the levels of
IL-1 were only 20 pg/mL, levels insufficient to stimulate OCL
formation in vivo.
However, although IL-6, IL-1, or lymphotoxin was undetectable in marrow
plasma from MM patients, freshly isolated bone marrow plasma from these
patients significantly stimulated OCL formation in human bone marrow
cultures. Furthermore, levels of OCL formation that were induced by the
OSF in these marrow plasma correlated (r = 0.7) with tumor burden, as
assessed by 2 microglobulin levels, in patients with
normal renal function. These data suggest that factors other than IL-6,
IL-1, and TNF- are implicated in the pathogenesis of myeloma bone disease.
Our results and those of other workers suggest that MIP-1 is a good
candidate for a possible OCL-stimulating factor in MM. In addition to
its proinflammatory activities in vitro, MIP-1 increases OCL
formation and OCL recruitment in rodent systems and is produced by
LCLs.13 MIP-1 also inhibits CD34+ cell
proliferation and stimulates phagocyte activity.28 We have
shown that MIP-1 also stimulates OCL formation in human bone marrow
cultures. We have demonstrated, using RNAse protection assay, that
MIP-1 is overexpressed in 3 of 4 MM patients when compared to normal
controls. Furthermore, the levels of MIP-1 were increased in the
bone marrow plasma of the majority of patients with active MM, compared
to patients with inactive disease. MIP-1 was not detected in the
peripheral blood plasma of patients with MM with active disease,
consistent with the observation that myeloma bone disease is a local
process. Thus, bone marrow plasma should contain much higher levels of
the factor(s) involved in myeloma bone disease than peripheral blood.
In our studies, the bone marrow samples were obtained in a single
aspiration and diluted with peripheral blood. Because peripheral blood
did not have elevated levels of MIP-1, the elevated marrow plasma
levels of MIP-1 we found in these patients underestimate the actual
levels of MIP-1 present in the marrow. Most importantly,
anti-MIP-1 blocked the OSF present in bone marrow plasma from 2 patients with MM.
Taken together, these data demonstrate that MIP-1 is an OSF that is
present in vivo in the marrow of the majority of patients with active
myeloma bone disease, that it is a stimulator of human OCL formation,
and that levels of MIP-1 correlate with the activity of myeloma bone
disease in these patients. These results support a role for MIP-1 as
a major mediator of the increased OCL activity in patients with MM.
| |
Acknowledgments |
We thank Bibi Cates for preparation of this manuscript and the staff of
the General Clinical Research Center, Audie L. Murphy Veterans
Administration Hospital, for their assistance in the care of our
patients with multiple myeloma and the collection of samples.
| |
Footnotes |
Submitted July 8, 1999; accepted March 2, 2000.
Supported by Research Funds from the Veterans Administration
(G.D.R.) and National Institutes of Health NCI Grants CA69136 (M.A.) and CA40035 (G.D.R.).
Reprints: Melissa Alsina, Research Service, 151 Audie L. Murphy
Veterans Administration Hospital, 7400 Merton Minter Boulevard, San
Antonio, TX 78284; e-mail: alsina{at}uthscsa.edu.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
References |
1.
Bergsagel D.
The incidence and epidemiology of plasma cell neoplasm.
Stem Cells.
1995;13:1-9[Abstract].
2.
Bataille R, Chappard D, Marcelli C, et al.
Mechanism of bone destruction in multiple myeloma. The importance of an unbalanced process in determining the severity of lytic bone disease.
J Clin Oncol.
1989;7:1909-1914[Abstract].
3.
Bataille R, Manolagas SC, Berenson JR.
Pathogenesis and management of bone lesions in multiple myeloma.
Hematol Oncol Clin North Am.
1997;11:349-361[Medline]
[Order article via Infotrieve].
4.
Klein B, Bataille R.
Cytokine network in human multiple myeloma.
Hematol Oncol Clin North Am.
1992;6:273-284[Medline]
[Order article via Infotrieve].
5.
Cozzolino F, Torcia M, Aldinucci D, et al.
Production of interleukin-1 by bone marrow myeloma cells.
Blood.
1989;74:380-387[Abstract/Free Full Text].
6.
Kawano M, Tanaka H, Ishikawa H, et al.
Interleukin-1 accelerates autocrine growth of myeloma cells through interleukin-6 in human myeloma.
Blood.
1989;73:2145-2148[Abstract/Free Full Text].
7.
Bataille R, Jourdan M, Zhang XG, Klein B.
Serum levels of interleukin-6, a potent myeloma cell growth factor, as a reflection of disease severity in plasma cell dyscrasias.
J Clin Invest.
1989;84:2008-2011.
8.
Garrett IR, Durie BGM, Nedwin GE, et al.
Production of the bone-resorbing cytokine lymphotoxin by cultured human myeloma cells.
N Engl J Med.
1987;317:526-532[Abstract].
9.
Kiss TL, Lipton JH, Bergsagel DE, et al.
Determination of IL-6, IL-1 and IL-4 in the plasma of patients with multiple myeloma.
Leuk Lymph.
1994;14:335-340[Medline]
[Order article via Infotrieve].
10.
Cook DN.
The role of MIP-1 alpha in inflammation and hematopoiesis.
J Leuk Biol.
1996;59:61-66[Abstract].
11.
Kukita T, Nomiyama H, Ohmoto Y, et al.
Macrophage inflammatory protein-1 (LD78) expressed in human bone marrow: its role in regulation of hematopoiesis and osteoclast recruitment.
Lab Invest.
1997;76:399-406[Medline]
[Order article via Infotrieve].
12.
Fuller K, Owens JM, Chambers TJ.
Macrophage inflammatory protein-alpha and IL-18 stimulate the motility but suppress the resorption of isolated rat osteoclasts.
J Immunol.
1995;154:6065-6072[Abstract].
13.
Tsujimoto T, Lisukov IA, Huang N, Mahmoud MS, Kawano MM.
Plasma cells induce apoptosis of pre-B cells by interacting with bone marrow stromal cells.
Blood.
1996;87:3375-3383[Abstract/Free Full Text].
14.
Devlin RD, Reddy SV, Savano R, Ciliberto G, Roodman GD.
IL-6 mediates the effects of IL-1 or TNF, but not PTHrP or 1,25-OH)2D3, on osteoclast-like cell formation in normal human bone marrow cultures.
J Bone Miner Res.
1998;13:393-399[Medline]
[Order article via Infotrieve].
15.
Fahley J, Buell D, Sox H.
Proliferation and differentiation of lymphoid cells. Studies with human lymphoid cell lines and immunoglobulin synthesis.
Ann N Y Acad Sci.
1971;190:221[Medline]
[Order article via Infotrieve].
16.
Matsuoka Y, Moore G, Yagi Y, Pressman D.
Production of free light chains of immunoglobulin by a hematopoietic cell line derived from a patient with multiple myeloma.
Proc Soc Exp Biol Med.
1967;125:1246[Medline]
[Order article via Infotrieve].
17.
Ritts RE, Ruiz-Arguelles A, Karin G, et al.
Establishment and characterization of a human non-secretory plasmacytoid cell line and its hybridization with human B cells.
Int J Cancer.
1983;31:133-141[Medline]
[Order article via Infotrieve].
18.
Olsson L, Kaplan HS.
Human-human hybridomas producing monoclonal antibodies of predefined antigenic specificity.
Proc Natl Acad Sci U S A.
1980;77:5429-5431[Abstract/Free Full Text].
19. Burk KH, Drewinko B, Trujillo JM, Ahearn MJ. Establishment of a human
plasma cell line in vitro. Cancer Res. 1978;2508-2513.
20.
Horton MA, Lewis D, McNulty K, Pringle JAS, Chambers TJ.
Monoclonal antibodies to osteoclastomas (giant cell bone tumors): definition of osteoclast-specific cellular antigen.
Cancer Res.
1985;45:5663-5669[Abstract/Free Full Text].
21.
Kukita T, McManus L, Miller M, Civin C, Roodman GD.
Osteoclast-like cells formed in long-term human bone marrow cultures express a similar surface phenotype as authentic osteoclasts.
Lab Invest.
1989;60:532-538[Medline]
[Order article via Infotrieve].
22.
Kurihara N, Bertolini D, Suda T, Akiyama T, Roodman GD.
IL-6 stimulates osteoclast-like multinucleated cell formation in long-term marrow cultures by inducing IL-1 release.
J Immunol.
1990;144:4226-4230[Abstract].
23.
Roodman GD, Kurihara N, Ohsaki Y, et al.
Interleukin-6: a potential autocrine/paracrine factor in Paget's disease of bone.
J Clin Invest.
1992;89:46-52.
24.
Mundy GR, Bertolini DR.
Bone destruction and hypercalcemia in plasma cell myeloma.
Semin Oncol.
1986;3:291-299.
25.
Lichtenstein A, Berenson J, Norman D, Chang MP, Carlile A.
Production of cytokines by bone marrow cells obtained from patients with multiple myeloma.
Blood.
1989;74:1266-1273[Abstract/Free Full Text].
26.
Lust JA, Donovan KA.
Novel therapeutic strategies. VIth International Workshop on Multiple Myeloma Syllabus.; 1997.
27.
Alsina M, Boyce B, Devlin R, et al.
Development of an in vivo model of human multiple myeloma bone disease.
Blood.
1996;87:1495-1501[Abstract/Free Full Text].
28.
Bonnet D, Lemoine FM, Najman A, Guigon M.
Comparison of the inhibitory effect of AcSDKP, TNF-alpha, TGF-beta, and MIP-1 alpha on marrow-purified CD34+ progenitors.
Exp Hematol.
1995;23:551-556[Medline]
[Order article via Infotrieve].
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A. E. Hoffman, T. Zheng, R. G. Stevens, Y. Ba, Y. Zhang, D. Leaderer, C. Yi, T. R. Holford, and Y. Zhu
Clock-Cancer Connection in Non-Hodgkin's Lymphoma: A Genetic Association Study and Pathway Analysis of the Circadian Gene Cryptochrome 2
Cancer Res.,
April 15, 2009;
69(8):
3605 - 3613.
[Abstract]
[Full Text]
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J. A. Burger, M. P. Quiroga, E. Hartmann, A. Burkle, W. G. Wierda, M. J. Keating, and A. Rosenwald
High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation
Blood,
March 26, 2009;
113(13):
3050 - 3058.
[Abstract]
[Full Text]
[PDF]
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O. Sezer
Myeloma Bone Disease: Recent Advances in Biology, Diagnosis, and Treatment
Oncologist,
March 1, 2009;
14(3):
276 - 283.
[Abstract]
[Full Text]
[PDF]
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N. Giuliani, G. Lisignoli, S. Colla, M. Lazzaretti, P. Storti, C. Mancini, S. Bonomini, C. Manferdini, K. Codeluppi, A. Facchini, et al.
CC-Chemokine Ligand 20/Macrophage Inflammatory Protein-3{alpha} and CC-Chemokine Receptor 6 Are Overexpressed in Myeloma Microenvironment Related to Osteolytic Bone Lesions
Cancer Res.,
August 15, 2008;
68(16):
6840 - 6850.
[Abstract]
[Full Text]
[PDF]
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J. Lorenzo, M. Horowitz, and Y. Choi
Osteoimmunology: Interactions of the Bone and Immune System
Endocr. Rev.,
June 1, 2008;
29(4):
403 - 440.
[Abstract]
[Full Text]
[PDF]
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S. L. Kominsky, S. M. Abdelmagid, M. Doucet, K. Brady, and K. L. Weber
Macrophage Inflammatory Protein-1{delta}: A Novel Osteoclast Stimulating Factor Secreted by Renal Cell Carcinoma Bone Metastasis
Cancer Res.,
March 1, 2008;
68(5):
1261 - 1266.
[Abstract]
[Full Text]
[PDF]
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S. T. Shu, M. V.P. Nadella, W. P. Dirksen, S. A. Fernandez, N. K. Thudi, J. L. Werbeck, M. D. Lairmore, and T. J. Rosol
A Novel Bioluminescent Mouse Model and Effective Therapy for Adult T-Cell Leukemia/Lymphoma
Cancer Res.,
December 15, 2007;
67(24):
11859 - 11866.
[Abstract]
[Full Text]
[PDF]
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S. Vallet, N. Raje, K. Ishitsuka, T. Hideshima, K. Podar, S. Chhetri, S. Pozzi, I. Breitkreutz, T. Kiziltepe, H. Yasui, et al.
MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts
Blood,
November 15, 2007;
110(10):
3744 - 3752.
[Abstract]
[Full Text]
[PDF]
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S. T. Pals, D. J. J. de Gorter, and M. Spaargaren
Lymphoma dissemination: the other face of lymphocyte homing
Blood,
November 1, 2007;
110(9):
3102 - 3111.
[Abstract]
[Full Text]
[PDF]
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E. Terpos, O. Sezer, P. Croucher, and M.-A. Dimopoulos
Myeloma bone disease and proteasome inhibition therapies
Blood,
August 15, 2007;
110(4):
1098 - 1104.
[Abstract]
[Full Text]
[PDF]
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T.A. Silva, G.P. Garlet, S.Y. Fukada, J.S. Silva, and F.Q. Cunha
Chemokines in Oral Inflammatory Diseases: Apical Periodontitis and Periodontal Disease
Journal of Dental Research,
April 1, 2007;
86(4):
306 - 319.
[Abstract]
[Full Text]
[PDF]
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S. Yaccoby, W. Ling, F. Zhan, R. Walker, B. Barlogie, and J. D. Shaughnessy Jr
Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo
Blood,
March 1, 2007;
109(5):
2106 - 2111.
[Abstract]
[Full Text]
[PDF]
|
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Y. Tanaka, M. Abe, M. Hiasa, A. Oda, H. Amou, A. Nakano, K. Takeuchi, K. Kitazoe, S. Kido, D. Inoue, et al.
Myeloma Cell-Osteoclast Interaction Enhances Angiogenesis Together with Bone Resorption: A Role for Vascular Endothelial Cell Growth Factor and Osteopontin
Clin. Cancer Res.,
February 1, 2007;
13(3):
816 - 823.
[Abstract]
[Full Text]
[PDF]
|
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P. G. Richardson, T. Hideshima, and K. C. Anderson
Plasma cell dyscrasias
ASH Self-Assessment Program,
January 1, 2007;
2007(1):
298 - 327.
[Full Text]
[PDF]
|
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E. Masih-Khan, S. Trudel, C. Heise, Z. Li, J. Paterson, V. Nadeem, E. Wei, D. Roodman, J. O. Claudio, P. L. Bergsagel, et al.
MIP-1{alpha} (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma
Blood,
November 15, 2006;
108(10):
3465 - 3471.
[Abstract]
[Full Text]
[PDF]
|
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G. D. Roodman
New potential targets for treating myeloma bone disease.
Clin. Cancer Res.,
October 15, 2006;
12(20):
6270s - 6273s.
[Abstract]
[Full Text]
[PDF]
|
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H. S. Yeh and J. R. Berenson
Treatment for myeloma bone disease.
Clin. Cancer Res.,
October 15, 2006;
12(20):
6279s - 6284s.
[Abstract]
[Full Text]
[PDF]
|
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B. Weinstock-Guttman, J. Hong, R. Santos, M. Tamano-Blanco, D. Badgett, K. Patrick, M. Baier, J. Feichter, E. Gallagher, N. Garg, et al.
Interferon-{beta} modulates bone-associated cytokines and osteoclast precursor activity in multiple sclerosis patients
Multiple Sclerosis,
September 1, 2006;
12(5):
541 - 550.
[Abstract]
[PDF]
|
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T. R. Halfdanarson, W. J. Hogan, and T. J. Moynihan
Oncologic Emergencies: Diagnosis and Treatment
Mayo Clin. Proc.,
June 1, 2006;
81(6):
835 - 848.
[Abstract]
[Full Text]
[PDF]
|
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T. Matsumoto and M. Abe
Myeloma-Bone Interaction: A Vicious Cycle
IBMS BoneKEy,
March 1, 2006;
3(3):
8 - 14.
[Abstract]
[Full Text]
[PDF]
|
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A. Badros, D. Weikel, A. Salama, O. Goloubeva, A. Schneider, A. Rapoport, R. Fenton, N. Gahres, E. Sausville, R. Ord, et al.
Osteonecrosis of the Jaw in Multiple Myeloma Patients: Clinical Features and Risk Factors
J. Clin. Oncol.,
February 20, 2006;
24(6):
945 - 952.
[Abstract]
[Full Text]
[PDF]
|
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|
|
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S. Yaccoby
The Phenotypic Plasticity of Myeloma Plasma Cells as Expressed by Dedifferentiation into an Immature, Resilient, and Apoptosis-Resistant Phenotype
Clin. Cancer Res.,
November 1, 2005;
11(21):
7599 - 7606.
[Abstract]
[Full Text]
[PDF]
|
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|
|
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T. Oshima, M. Abe, J. Asano, T. Hara, K. Kitazoe, E. Sekimoto, Y. Tanaka, H. Shibata, T. Hashimoto, S. Ozaki, et al.
Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2
Blood,
November 1, 2005;
106(9):
3160 - 3165.
[Abstract]
[Full Text]
[PDF]
|
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H. Shibata, M. Abe, K. Hiura, J. Wilde, K. Moriyama, T. Sano, K.-i. Kitazoe, T. Hashimoto, S. Ozaki, S. Wakatsuki, et al.
Malignant B-Lymphoid Cells with Bone Lesions Express Receptor Activator of Nuclear Factor-{kappa}B Ligand and Vascular Endothelial Growth Factor to Enhance Osteoclastogenesis
Clin. Cancer Res.,
September 1, 2005;
11(17):
6109 - 6115.
[Abstract]
[Full Text]
[PDF]
|
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B. O. Oyajobi, C. M. Shipman, and G. R. Mundy
Recent Insights into Myeloma Bone Disease
IBMS BoneKEy,
May 1, 2005;
2(5):
17 - 25.
[Full Text]
[PDF]
|
|
|
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|
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O. H. Ryu, S. J. Choi, E. Firatli, S. W. Choi, P. S. Hart, R.-F. Shen, G. Wang, W. W. Wu, and T. C. Hart
Proteolysis of Macrophage Inflammatory Protein-1{alpha} Isoforms LD78{beta} and LD78{alpha} by Neutrophil-derived Serine Proteases
J. Biol. Chem.,
April 29, 2005;
280(17):
17415 - 17421.
[Abstract]
[Full Text]
[PDF]
|
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|
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|
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L. Yin
Chondroitin Synthase 1 Is a Key Molecule in Myeloma Cell-Osteoclast Interactions
J. Biol. Chem.,
April 22, 2005;
280(16):
15666 - 15672.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
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T. Matsumoto and M. Abe
The Importance of Notch Signaling in Myeloma Cell-Osteoclast Interactions
IBMS BoneKEy,
February 1, 2005;
2(2):
7 - 10.
[Full Text]
[PDF]
|
|
|
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M. Abe, K. Hiura, J. Wilde, A. Shioyasono, K. Moriyama, T. Hashimoto, S. Kido, T. Oshima, H. Shibata, S. Ozaki, et al.
Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion
Blood,
October 15, 2004;
104(8):
2484 - 2491.
[Abstract]
[Full Text]
[PDF]
|
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T. Kukita, N. Wada, A. Kukita, T. Kakimoto, F. Sandra, K. Toh, K. Nagata, T. Iijima, M. Horiuchi, H. Matsusaki, et al.
RANKL-induced DC-STAMP Is Essential for Osteoclastogenesis
J. Exp. Med.,
October 4, 2004;
200(7):
941 - 946.
[Abstract]
[Full Text]
[PDF]
|
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Y. Okamatsu, D. Kim, R. Battaglino, H. Sasaki, U. Spate, and P. Stashenko
MIP-1 gamma promotes receptor-activator-of-NF-kappa-B-ligand-induced osteoclast formation and survival.
J. Immunol.,
August 1, 2004;
173(3):
2084 - 2090.
[Abstract]
[Full Text]
[PDF]
|
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|
|
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G. D. Roodman
Mechanisms of Bone Metastasis
N. Engl. J. Med.,
April 15, 2004;
350(16):
1655 - 1664.
[Full Text]
[PDF]
|
|
|
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P. A. Croonquist, M. A. Linden, F. Zhao, and B. G. Van Ness
Gene profiling of a myeloma cell line reveals similarities and unique signatures among IL-6 response, N-ras-activating mutations, and coculture with bone marrow stromal cells
Blood,
October 1, 2003;
102(7):
2581 - 2592.
[Abstract]
[Full Text]
[PDF]
|
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B. O. Oyajobi, G. Franchin, P. J. Williams, D. Pulkrabek, A. Gupta, S. Munoz, B. Grubbs, M. Zhao, D. Chen, B. Sherry, et al.
Dual effects of macrophage inflammatory protein-1{alpha} on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease
Blood,
July 1, 2003;
102(1):
311 - 319.
[Abstract]
[Full Text]
[PDF]
|
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F. Magrangeas, V. Nasser, H. Avet-Loiseau, B. Loriod, O. Decaux, S. Granjeaud, F. Bertucci, D. Birnbaum, C. Nguyen, J.-L. Harousseau, et al.
Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease
Blood,
June 15, 2003;
101(12):
4998 - 5006.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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S. Lentzsch, M. Gries, M. Janz, R. Bargou, B. Dorken, and M. Y. Mapara
Macrophage inflammatory protein 1-alpha (MIP-1alpha ) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells
Blood,
May 1, 2003;
101(9):
3568 - 3573.
[Abstract]
[Full Text]
[PDF]
|
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U. Heider, C. Langelotz, C. Jakob, I. Zavrski, C. Fleissner, J. Eucker, K. Possinger, L. C. Hofbauer, and O. Sezer
Expression of Receptor Activator of Nuclear Factor {kappa}B Ligand on Bone Marrow Plasma Cells Correlates with Osteolytic Bone Disease in Patients with Multiple Myeloma
Clin. Cancer Res.,
April 1, 2003;
9(4):
1436 - 1440.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Sezer, U. Heider, I. Zavrski, C. A. Kuhne, and L. C. Hofbauer
RANK ligand and osteoprotegerin in myeloma bone disease
Blood,
March 15, 2003;
101(6):
2094 - 2098.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Abe, K. Hiura, J. Wilde, K. Moriyama, T. Hashimoto, S. Ozaki, S. Wakatsuki, M. Kosaka, S. Kido, D. Inoue, et al.
Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma
Blood,
August 28, 2002;
100(6):
2195 - 2202.
[Abstract]
[Full Text]
[PDF]
|
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|
|
|
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S. A. Ely and D. M. Knowles
Expression of CD56/Neural Cell Adhesion Molecule Correlates with the Presence of Lytic Bone Lesions in Multiple Myeloma and Distinguishes Myeloma from Monoclonal Gammopathy of Undetermined Significance and Lymphomas with Plasmacytoid Differentiation
Am. J. Pathol.,
April 1, 2002;
160(4):
1293 - 1299.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. C. Anderson, J. D. Shaughnessy Jr., B. Barlogie, J.-L. Harousseau, and G. D. Roodman
Multiple Myeloma
Hematology,
January 1, 2002;
2002(1):
214 - 240.
[Abstract]
[Full Text]
|
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P. I. Croucher, C. M. Shipman, J. Lippitt, M. Perry, K. Asosingh, A. Hijzen, A. C. Brabbs, E. J. R. van Beek, I. Holen, T. M. Skerry, et al.
Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma
Blood,
December 15, 2001;
98(13):
3534 - 3540.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
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|
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G. D. Roodman
Biology of Osteoclast Activation in Cancer
J. Clin. Oncol.,
August 1, 2001;
19(15):
3562 - 3571.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
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J.-H. Han, S. J. Choi, N. Kurihara, M. Koide, Y. Oba, and G. D. Roodman
Macrophage inflammatory protein-1{alpha} is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor {kappa}B ligand
Blood,
June 1, 2001;
97(11):
3349 - 3353.
[Abstract]
[Full Text]
[PDF]
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K. C. Anderson, R. A. Kyle, W. S. Dalton, T. Landowski, K. Shain, R. Jove, L. Hazlehurst, and J. Berenson
Multiple Myeloma: New Insights and Therapeutic Approaches
Hematology,
January 1, 2000;
2000(1):
147 - 165.
[Abstract]
[Full Text]
[PDF]
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Top
Abstract
Introduction