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NEOPLASIA
From the First Department of Internal Medicine, School
of Medicine, Department of Orthodontics, School of Dentistry, and First
Department of Pathology, School of Medicine, University of Tokushima,
and Tokushima Prefectural Hospital Kaifu, Tokushima, Japan.
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)-1 Multiple myeloma (MM) is a plasma cell malignancy
characterized by an almost exclusive accumulation in the bone marrow,
secretion of monoclonal immunoglobulin, and a suppression of normal
immunoglobulin production and hematopoiesis, especially that of the
erythroid lineage.1,2 Another important clinical feature
of MM is a marked stimulation of osteoclastic bone resorption, which
causes the most debilitating clinical symptoms including intractable bone pain, disabling multiple fractures, and hypercalcemia. The aggressive bone destruction has significantly contributed to its poor
prognosis, which has barely been improved since the introduction of the
melphalan and prednisolone therapy in the 1960s despite the development
of potent chemotherapeutic regimens.1,3 In our laboratory,
new antitumor agents are now under development including
immunotherapies with MM-specific monoclonal antibodies (mAbs).4,5 However, elucidation of the molecular mechanism of bone destruction is critical to develop an effective way to improve
survival as well as quality of life of patients with MM.
Cytokines with potent bone-resorbing activity such as interleukin 6 (IL-6) and IL-1 To clarify the mechanism of development of MM bone lesions, we searched
for MM-derived factors responsible for enhancement of osteoclastic bone
resorption. We hereby present evidence that C-C chemokines, macrophage
inflammatory protein (MIP)-1 Chemicals
Cells and cultures
All procedures involving human specimens were performed according to the protocol approved by the Institutional Review Board for human protection. To obtain human marrow stromal cells, bone marrow mononuclear cells were isolated by Ficoll-Hypaque density gradient centrifugation (Pharmacia LKB Biotechnology, Uppsala, Sweden) from heparinized bone marrow blood drawn from patients with MM under written informed consents. These marrow cells were depleted of monocytes and myeloid cells by incubation with anti-CD11b, CD14, and CD33 mAb and subsequent addition of Dynabeads M-450 goat anti-mouse IgG (Dynal, Great Neck, NY) according to the manufacturer's instructions, and were resuspended in Iscove modified Dulbecco medium (IMDM) supplemented with 12.5% fetal calf serum (FCS; Whittaker Bioproducts, Walkersville, MD), 12.5% horse serum (Whittaker), 50 U/mL penicillin, and 50 µg/mL streptomycin (Gibco BRL, Rockville, MD). The adherent marrow stromal cells were serially passed at confluency, using 0.05% trypsin/0.53 mM EDTA (ethylenediaminetetraacetic acid; Gibco BRL), to obtain a homogeneous population of spindle-shaped cells. These cells expressed vimentin, collagen type I and III, but not endothelial cell antigens such as collagen type IV or factor VIII antigen, or hematopoietic cell surface antigens (data not shown). Myeloma cell-rich fractions were prepared from bone marrow mononuclear cells by negative selection using Dynabeads M-450 goat antimouse IgG (Dynal) and a cocktail of mAbs including anti-CD3, CD4, CD8, CD19, CD11b, CD14, CD16, and CD33 mAbs. Highly purified myeloma cells were subsequently prepared by a positive selection using magnetic beads and a human myeloma cell-specific anti-HM1.24 mAb raised in our laboratory.16 Purity of thus obtained myeloma cells was more than 95%. Myeloma cells were cultured in a serum-free medium containing a 1:1 mixture of Ham F-12 medium and Dulbecco modified Eagle medium (GIT medium, Wako Pure Chemicals, Osaka, Japan). In vitro osteoclastogenesis For in vitro osteoclastogenesis, osteoclast precursors were first prepared from unfractionated bone cells according to the previously described procedure19 with a slight modification. In brief, minced long bones of 5-day-old white rabbits were agitated by vortexing, and bone particles were removed by sedimentation for 30 seconds in Eagle minimal essential medium (MEM; Life Technologies, Gaithersburg, MD). After centrifugation at 300g for 3 minutes, two thirds of the supernatant from the top was removed. Remaining fractions were used as a source of osteoclast precursors. Thus obtained preosteoclast-rich fractions of rabbit bone cells were seeded in 96-well plates at 5 × 104 cells/well and cultured for 96 hours in MEM containing 3% fetal bovine serum (FBS) in the absence or presence of various factors or conditioned media. For coculture experiments, MM cells at 2 × 103 cells/well were added into the cultures. Cocultures of mouse stromal cell line, ST-2, and a preosteoclastic cell line, C7,18 were performed as previously described. Briefly, 3 × 104 C7 and 1 × 104 ST-2 cells/well were cultured in 96 well-culture plates in MEM plus 10% FBS in the presence of 100 nM dexamethasone
and test reagents. After 8 days, the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) were counted as described below.
Assays for osteoclastogenesis and bone resorption To evaluate osteoclastlike cell formation, cells were stained for TRAP using leukocyte acid phosphatase kit (Sigma, St Louis, MO) and the number of TRAP+ MNCs were counted. For resorption assays, cells were cultured on bone slices from calf femur for 96 hours. Cells were then brushed off and bone slices were stained with acid hematoxylin for 5 minutes to visualize resorption pits. For quantification, the number of mesh squares covering the pits was counted using a microscope with a mesh glass installed in the ocular lens.Collection of conditioned media and measurement of cytokine secretion The MM cell lines or primary MM cells from patients were cultured at 5 × 105 cells/mL for 2 days and conditioned media were harvested. MIP-1 and MIP-1 levels were measured using
Quantikine MIP-1 and MIP-1 enzyme immunoassay kits, respectively
(R & D Systems). IL-1 and IL-6 levels were quantified using
TiterZyme IL-1 and IL-6 enzyme immunoassay kits, respectively
(Perseptive Diagnostic, Cambridge, MA), according to the
manufacturer's instructions.
Flow cytometry Cell preparation and staining for flow cytometry were performed as described previously.19 Approximately 106 cells were incubated with saturating concentrations of FITC-conjugated mAbs on ice for 1 hour. For indirect fluorescence staining, cells were incubated first with primary antibodies on ice for 1 hour, washed, and then incubated with FITC-conjugated secondary antibodies on ice for 30 minutes. Samples were analyzed by flow cytometry using EPICS-Profile (Coulter Electronics, Hialeah, FL).Cell adhesion assays rhVCAM-1 was applied to 24-well culture plates at 10 µg/mL in Ca/Mg-free phosphate-buffered saline (PBS) and incubated at 4°C overnight. Nonspecific binding sites were subsequently blocked with 3% human serum albumin (HSA) in Ca/Mg-free PBS (Green-Cross, Osaka, Japan) for 2 hours at 37°C. MM cells were labeled with 10 µg/mL fluorescent dye (BCECF-AM; Dojindo, Kumamoto, Japan) in GIT medium for 2 hours at 37°C. A total of 1 × 106 MM cells were washed, resuspended in GIT medium with or without the indicated antibodies at a saturating concentration (20 µg/mL), plated onto prewashed rhVCAM-1-coated plates, and incubated at 4°C for 30 minutes, and then rapidly warmed to 37°C and further incubated for 30 minutes. After gently washing 4 times with GIT medium at room temperature, fluorescence intensity of lysed adherent cells was measured as previously described.20RNA analysis Total RNA was extracted from various cells using TRIZOL reagent (Gibco BRL, Rockville, MD). For reverse transcription-polymerase chain reaction (RT-PCR), 2 µg total RNA was reverse transcribed with Superscript II (Gibco) in a 20-µL reaction. Two microliters of the 20-µL reaction was used for the subsequent PCR analysis with cycles of 95°C for 30 seconds, 58°C for 30 seconds, and 72°C for 30 seconds. Primers used are as follows: 5'-gaatcatgcaggtctccactg-3' (nucleotides 79-99) and 5'-ctctaggtcgctgacatatttc-3' (nucleotides 350-329) for human MIP-1; 5'-gtgactgtcctgtctctcctc-3' (nucleotides 121-141) and 5'-gttccaggtcatacacgtactc-3' (nucleotides 379-358) for
human MIP-1; 5'-agtattcacagggctctatcac-3' (nucleotides 316-337) and
5'-atggcctggtctagtctattag-3' (nucleotides 846-825) for mouse CCR5;
5'-agtgtcaagtccaatctatgac-3' (nucleotides 369-390) and
5'-tatggaaaatgagagctgcagg-3' (nucleotides 908-887) for human CCR5;
5'-tgtcttcaccaccatggagaagg-3' (nucleotides 340-362) and
5'-gtggatgcagggatgatgttctg-3' (nucleotides 672-650) for mouse and human
glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Amplified
products were dissolved in a 2% agarose gel and visualized with
ethidium bromide staining.
For RNase protection assay, a fragment of mouse RANK ligand cDNA
(nucleotides 480-1030) obtained by RT-PCR was subcloned into pBluescript SKII(+) (Stratagene, La Jolla, CA). The resultant plasmid
was linearized and used for generation of a cRNA probe using MAXIscript
in vitro transcription kit (Ambion, Austin, TX). The control
probe template for mouse
Stimulatory effect of MM cells on osteoclast formation and function in vitro ARH77 is an EBV-transformed human B lymphoblastic cell line that is able to develop MM-like destructive bone lesions when transplanted into SCID mice. As an initial step to investigate the mechanism of MM-induced bone resorption, we examined whether or not ARH77 cells had the ability to stimulate osteoclast formation and function in vitro. When these cells were cocultured with osteoclast precursors from rabbit bone, both formation of TRAP+ multinucleated osteoclastlike cells and their activity to form resorption pits were increased to approximately 3-fold (Figure 1A). The fact that the induction of OCL formation occurred to nearly the same extent as the increase in resorption suggested that the main effect of MM cells was enhancement of osteoclast differentiation rather than direct activation of mature osteoclasts. Similar results were obtained with another human myeloma cell line, IM-9, as well as primary myeloma cells purified from bone marrow samples of 2 patients who had radiographically demonstrated bone lesions. In contrast, addition of RPMI8226 cells that were incapable of forming bone lesions in the SCID mouse model (data not shown) had no effects (Figure 1A). Thus, we have established an in vitro model system where MM cells activate osteoclastic bone resorption in the bone marrow milieu.
Soluble factor- and contact-dependent stimulation of osteoclast formation and function by MM cells We next determined whether soluble factors secreted by MM cells contribute to the ability of these cells to enhance OCL formation and function. As shown in Figure 1B, conditioned media from ARH77 myeloma cell cultures increased OCL formation and function to more than 2-fold. Consistent with the potent osteoclastogenic activity of the conditioned media, inhibition of direct cellular interactions between MM and rabbit bone cells by membrane filters resulted in only 20% reduction in the MM cell effect compared with cocultures of these 2 cell populations (Figure 1B). Therefore, although cell-cell contacts with bone cells may contribute to some extent, a large part of the MM cell effect is accounted for by soluble factors secreted by MM cells at least in this in vitro system.Production of osteoclastogenic chemokines MIP-1 and IL-6,
well-known stimulators of osteoclast differentiation, in the MM
cell-conditioned media. However, these factors were not produced at
detectable levels by ARH77, IM-9, or primary cells from the 2 patients
(data not shown), all of which potently stimulated osteoclastogenesis
in cocultures with marrow cells under our experimental conditions. We
then turned to C-C chemokines, MIP-1 and MIP-1, both of which
dose-dependently up-regulated osteoclast formation and function when
added to the rabbit bone cell cultures (Figure 2). We found that 7 MM cell lines
including ARH77, IM9, TSPC-1, MPC, NPC, OPC, and U266 secreted large
amounts of both MIP-1 and MIP-1 in culture supernatants (Table
1). Expression of MIP-1 and MIP-1
by these cell lines except MPC and NPC were also confirmed at the mRNA
levels (Figure 3). In contrast, RPMI8226
cells, which are incapable of enhancing bone resorption in vitro or
forming bone lesions in vivo, did not produce detectable amounts of
MIP-1 and MIP-1 (Table 1 and Figure 3). MIP-1 and MIP-1
were also secreted by MM cells freshly isolated from 20 and 21 of 28 patients, respectively. Furthermore, MM cells from patients with
multiple bone lesions secreted an apparently higher amount of MIP-1
than those from patients with less advanced bone involvement (Figure 4), demonstrating a clinical correlation
between severity of bone lesions and MIP-1 production by MM cells. On
the average, concentrations of MIP-1 and MIP-1 in culture
supernatants of isolated MM cells were 14 ± 7 (mean ± SD) and
24 ± 13 pg/mL, respectively, in patients with no or a single bone
lesion (n = 8); and 2417 ± 822 and 1462 ± 845, respectively, in
those with 2 or more bone lesions (n = 20). Collectively, these
results suggested that osteoclastogenic chemokines MIP- and MIP-1
are constitutively secreted by a majority of MM cells and further
implied that they may play a role in the development of MM bone lesions
because MIP-1 production correlated well with the ability of MM cells
to enhance osteoclastic bone resorption in the in vitro cocultures with
rabbit bone cells (Figure 1) and to cause bone destruction in a mouse
myeloma model (Table 1 and Figure 3) and in MM patients (Figure
4).
Inhibition of the MM cell-induced osteoclastogenesis by
neutralizing antibodies against MIP-1 and MIP-1 to
the MM-induced bone resorption, we next examined the effect of
neutralizing antibodies against MIP-1 and MIP-1 on the osteoclast induction by MM cells. As shown in Figure
5, the stimulatory effect of MM
cell-conditioned media on OCL formation was almost completely abrogated
by the addition of antibodies against MIP-1 and MIP-1 in
combination. Near-total inhibition of the osteoclast induction by these
antibodies was also observed in cocultures with MM cells including
ARH77, IM-9, and the same populations of primary MM cells from the 2 patients shown in Figure 1A (Figure 5). Similar results were also
obtained with another EBV myeloma cell line, U266. In
contrast, neutralizing antibodies against IL-1 or IL-6 had no
effects on the osteoclastogenic activities of these MM cells (data not
shown). These results suggested that osteoclastogenic effects of MM
cells were largely dependent on MIP-1 and MIP-1 in the bone
marrow milieu. To examine if the effects of these chemokines were
mediated by a specific chemokine receptor, we tested the ability of a
blocking antibody against a chemokine receptor, CCR5. CCR5 has been
shown to bind both MIP-1 and MIP-1 and is likely to be a major
receptor for these chemokines.21 An anti-CCR5 blocking
antibody also inhibited ARH77- and U266-induced OCL formation to a
large extent (Figure 5). However, the suppression of OCL formation was
significantly less than that by antibodies against MIP-1 and
MIP-1, implying that other chemokine receptors may also mediate the
effect of MIP-1 and MIP-1 on OCL formation. Taken together, these
results suggest that osteoclast induction by MM cells is in large part
mediated by MIP-1 and MIP-1, which are secreted by MM cells and
which mainly act via a chemokine receptor, CCR5.
Expression of CCR5 on bone marrow stromal and myeloma cells Given the fact that the effect of MM cells is largely dependent on CCR5, we next examined its expression on the cell surface of marrow stromal and myeloma cells by FACS analysis. The results indicated that CCR5 was expressed in both a human marrow stromal cell line KM102 and a myeloma cell line ARH77 as well as primary MM cells from patients (Figure 6A). As shown in Figure 6B, the expression of CCR5 in these cells was also confirmed at the mRNA level by RT-PCR analysis. Therefore, both marrow stromal and myeloma cells are potential targets of MIP-1 and MIP-1.
Dependency of MM cell-induced osteoclastogenesis on RANK ligand expression by stromal cells Expression of CCR5 on the surface of marrow stromal cells led us to hypothesize that the osteoclastogenic effect of MIP-1 and
MIP-1 is mediated by stromal cells. Critical roles of
stromal/osteoblastic cells in osteoclast differentiation have been
established. Recent studies have identified RANK ligand, a tumor
necrosis factor family member, as a key molecule mediating
osteoclastogenic effects of a large repertoire of bone resorptive
cytokines and hormones such as parathyroid hormone (PTH),
1,25-dihydroxyvitamin D, and IL-6.22-24 They first
stimulate stromal/osteoblastic cells to express RANK ligand, which then
interacts with its cognate receptor RANK expressed on the cell surface
of osteoclast progenitors to induce their differentiation. Therefore,
we next examined whether or not the MM cell effect was dependent on
RANK ligand expression by stromal cells by testing inhibitory effects
of OPG,25,26 a decoy receptor of RANK ligand on MM
cell-induced OCL formation. As shown in Figure 7, the osteoclastogenic activity of ARH77
cells as well as MIP-1 and MIP-1 was almost completely inhibited
by OPG in rabbit bone cell cultures. Furthermore, MIP-1 and MIP-1
directly induced RANK ligand expression by a mouse marrow stromal cell
line, ST-2, which expressed CCR5 in the presence of a suboptimal
concentration (0.1 nM) of 1,25-dihydroxyvitamin D3
(Figure 8A). The induction of RANK ligand
in ST-2 cells was in parallel with the stimulation of osteoclast
differentiation in cocultures with a mouse preosteoclast cell line, C7
(Figure 8B), confirming its functional significance. Neither MIP-1
nor MIP-1 was able to induce osteoclast differentiation when C7
cells were cultured alone (data not shown), although CCR5 was expressed
not only by ST-2 but also C7 cells (Figure 6). Taken together, these
results suggest that up-regulation of stromal cell RANK ligand
expression by MIP-1 and MIP-1, probably via CCR5, may be involved
in the mechanisms whereby MM cells enhance osteoclastic bone
resorption.
MIP-1 Critical roles of MIP-1 We have demonstrated that both MIP-1 Although our results suggest that soluble factors secreted by MM cells
play substantial roles in osteoclast induction in the in vitro system
used in the present study, direct interactions between MM cells and
bone marrow components should also contribute significantly to MM
cell-induced bone resorption. It was at first surprising to us that
anti-MIP-1 In addition to their osteoclast-inductive capacity, MIP-1 In conclusion, evidence presented herein suggests that MIP-1
We would like to thank Dr T. Higashio in Snow Brand Milk Products (Tochigi, Japan) for donating osteoprotegerin, Dr K. Harigaya (Chiba University, Chiba, Japan) for KM102, and Dr S. I. Hayashi (Tottori University, Tottori, Japan) for C7.
Submitted June 26, 2001; accepted May 8, 2002.
Supported by a Grant-in-Aid for Cancer Research (9-22) from the Ministry of Health, Labor and Welfare of Japan, and Grants-in-Aid for Scientific Research on Priority Areas (B) for T.M., for Scientific Research (B) for T.M., and for Encouragement of Young Scientists for D.I. from the Ministry of Education, Science, Sports and Culture of Japan.
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.
Reprints: Daisuke Inoue, First Department of Internal Medicine, University of Tokushima School of Medicine, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; e-mail: inoued{at}clin.med.tokushima-u.ac.jp.
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| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
and MIP-1
in the development of osteolytic lesions in multiple myeloma
Top
Abstract
Introduction
B (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1
, IgA
