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Departments of
*
Microbiology,
Oral Maxillo-Facial Surgery, and
Pediatrics, Saga Medical School, Saga, Japan; and
§
Department of Second Anatomy, Faculty of Dentistry, Kyushu University, Fukuoka, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, its activity was not abolished by addition of
anti-TNF- Ab. Interestingly, IL-2 and IL-7, which utilize some
IL-15R components, had no effect on osteoclast differentiation, but
pretreatment with IL-2 or IL-7 of bone marrow cells before the addition
of IL-15 inhibited the enhancing activity of IL-15. In summary, IL-15
has a novel activity to stimulate the differentiation of osteoclast
progenitors into preosteoclasts, which cannot be replaced by IL-2 but
may use components in common with IL-2R to mediate its
effects. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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c, to elicit
signals in these cells 1, 2, 3, 4, 5 . However, differences have been found in
the range of possible target cells and functions between IL-15 and
IL-2. Besides ß and c, IL-15 binds with high affinity to a unique
component, IL-15R, which is distinct from IL-2R 6 . Compared
with the mRNA expression of IL-2R, that of IL-15R showed a much
wider cellular distribution, suggesting that IL-15 has the ability to
exert various effects on many types of cells. For NK cell
differentiation, it is thought that IL-2 is not required but IL-15 is
7 . In addition, Tagaya et al. 8 recently found that IL-15 could
stimulate the proliferation of mast cells in the absence of IL-2R,
ß, and IL-15R using a novel unique receptor system. However,
little is known about those functions of IL-15 not shared by IL-2.
Osteoclasts are bone-resorptive cells that have a crucial role in
physiological bone remodeling 9 and also function in the local bone
destruction that occurs in association with chronic inflammatory
diseases 10 . Diseases such as rheumatoid arthritis have been
associated with an accumulation of proinflammatory cytokines such as
IL-1, IL-6, TNF-, and IL-8 11, 12, 13, 14, 15, 16, 17 , some of which likely mediate
local bone destruction by stimulating osteoclasts or osteoclast
differentiation. In fact, IL-6 was found to stimulate
osteoclastogenesis in an in vitro study 18 . Recently, McInnes et al.
19 reported the presence of high concentrations of IL-15 in
rheumatoid arthritis fluid, suggesting that IL-15 plays a role in
pathological bone destruction.
In the present study, we investigated the possible role of IL-15 in osteoclast differentiation. Osteoclasts are hematopoietic in origin, and these multinucleated cells are formed by fusion of mononuclear preosteoclasts 20 . We have recently developed two types of rat bone marrow culture systems in which the process of osteoclast development could be separated. In one of these systems, multinucleated osteoclast-like cells (MNCs)3 are formed 21 , while in the other, mononuclear preosteoclast-like cells (POCs) are formed from stroma-free cultures in the presence of conditioned medium of osteoblastic cells 22 . The POCs have several osteoclast characteristics including the expression of tartrate-resistant acid phosphatase (TRAP), calcitonin receptor (CTR), and Kat1, a rat osteoclast-specific Ag 23 . Here we show that IL-15 has the novel activity of enhancing the osteoclastogenesis by stimulating the formation of preosteoclasts, an activity not shared by IL-2.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male Sprague Dawley rats age 5–6 wk were purchased from SEAC
Yoshitomi (Fukuoka, Japan). 1,25-Dihydroxyvitamin D3
(1,25(OH)2D3) was purchased from Biomol
(Plymouth Meeting, PA). Human rIL-15, mouse anti-human IL-15 mAb
(M111), and human rIL-7 were purchased from Genzyme (Cambrige, MA), and
rat rIL-2 was purchased from Serotec (Bankside, Oxford, U.K.).
Anti-murine TNF--neutralizing Ab was obtained from R&D systems
(Minneapolis, MN). Indomethacin, salmon calcitonin (sCT), and a
cytochemical staining kit for TRAP staining were obtained from Sigma
(St. Louis, MO). 125I-labeled sCT was purchased from
Amersham (Little Chalfont, U.K.). NR-M2 emulsion, Konicadol X,
and Konicafix were obtained from Konica (Tokyo, Japan).
Whole bone marrow cell cultures
For the formation of MNCs, bone marrow cells isolated from
tibias and femurs of rats were cultured in -MEM containing 15% FCS
in the presence of 10-8 M
1,25(OH)2D3 and 10% (v/v) heat-treated
conditioned medium derived from rat osteoblastic cell line ROS17/2.8
(htROSCM), as described by Kukita et al. 21 . Various concentrations
of IL-15 were added to the cultures. After 3 days of culture, the cells
were fixed and then stained for TRAP, a marker enzyme for osteoclasts,
using a commercial kit. TRAP-positive cells with more than three nuclei
were counted.
Stroma-free bone marrow cell cultures
For the formation of POCs, adherent stromal cells were
eliminated from bone marrow cells using a Sephadex G-10 column, and
nonadherent bone marrow cells were cultured in the presence of
10-8 M 1,25(OH)2D3 and 10%
htROSCM as described by Kukita et al. 22 . Cells (2 x
105) were cultured in 96-well culture plates (Falcon,
Lincoln Park, NJ) in the presence or absence of various concentrations
of cytokines and mAb for the indicated times. After 4 days of culture,
the cells were fixed and then stained with TRAP or with the
osteoclast-specific mAb Kat1 23 . After the staining, the presence of
CTR in some cultures was confirmed by autoradiography. In some
experiments, nonadherent bone marrow cells were further purified on a
Sephadex G-10 column once more to eliminate stromal cells completely.
These purified nonadherent bone marrow cells did not form colonies of
stromal cells after 14 days of culture. Because there was no
significant difference in the osteoclastogenesis-enhancing activity of
IL-15 when purified nonadherent bone marrow cells or nonadherent bone
marrow cells were used, nonadherent bone marrow cells were used to form
POCs, except in the experiment of Fig. 1
B.
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Immunostaining with Kat1 was performed as described 23 . Briefly, the cells were incubated with mAb Kat1 for 45 min and fixed with 2% paraformaldehyde for 20 min at room temperature. After blocking with 3% goat serum for 60 min, the cells were incubated with biotinylated anti-mouse IgM as the second Ab for 30 min and then stained using a Vectastain ABC-AP kit (Vector, Burlingame, CA) according to the manufacturer’s instructions.
Preparation of rat primary osteoblasts
Rat primary osteoblasts were isolated by sequential digestion
from the calvariae of Sprague Dawley rats, according to the method of
Takahashi et al. 24 . The cells were cultured in -MEM containing
10% FCS in 100-mm culture dishes at 3 x 105
cells/dish. After 4 days of culture, the cells were trypsinized and
used as primary osteoblasts.
Coculture and dentine resorption assay
Bone resorption assays were performed according to the method of
Hata et al. 25 . Nonadherent bone marrow cells (1x106 in
500 µl of -MEM containing 15% FCS) seeded into 24-well culture
plates in the presence of 10% htROSCM with or without 100 ng/ml IL-15
for 5 days. Then rat primary osteoblasts (1x103
cells/well) were added to each well. After 4 days of culture, cells
were detached from the culture plates with 0.05% trypsin and 0.02%
EDTA in PBS, followed by replating onto human dentine, which were then
incubated in -MEM containing 15% FCS for 7 days. After the end
of culture, the resorption pits were examined with a JEOL
JSM-5200LV scanning electron microscope as described previously
26 .
125I-labeled sCT binding assay
CTR were detected by autoradiography using
125I-labeled sCT as described 22 . Briefly, the cells were
rinsed once with -MEM containing 0.1% BSA and incubated with 1
µCi/ml 125I-labeled sCT (74 TBq/mmol) at room temperature
for 2 h in the absence or presence of excess sCT (1 µg/ml).
After the cells were rinsed three times with -MEM containing 0.1%
BSA, they were fixed with 0.1 M cacodylate buffer (pH 7.3) containing
2% formaldehyde and 2% glutaraldehyde for 10 min. The cells were then
washed with -MEM containing 0.1% BSA and were stained for TRAP.
Subsequently, the bottoms of the wells were cut out from the culture
plate, dipped in NR-M2 emulsion, and air dried. After exposure for 2–3
wk at 4°C, autoradiographs were developed with Konicadol X and fixed
with Konicafix.
Detection of CTR mRNA by RT-PCR
Nonadherent bone marrow cells (1.1 x 107) were
cultured in 60-mm tissue culture dishes (Falcon) (5.7 ml/dish) in the
presence of 10-8 M 1,25(OH)2D3,
10% (v/v) htROSCM, and various concentrations of IL-15 for 4 days.
Total RNA was extracted by using a commercial kit (Isogen, Nippon Gene,
Toyama, Japan), and single-stranded cDNA was synthesized by using a
RT-PCR kit (Takara, Japan). The cDNA was amplified using specific
primers for rat CTR mRNA as described 27 . A 518-bp (C1a isoform) or
629-bp (C1b isoform) fragment of CTR cDNA was amplified using primers
(5'-AAGAACATGTT(C/T)CT(C/G/T)ACTTA-3', nucleotides 625–644, and
5'-ACAAACTGGA(T/C)(T/G)CCCAGCAGGGGCAC-3', nucleotides
1288–1253). The PCR products were separated on a 1% agarose gel,
transferred to a nylon membrane (Gene Screen, NEN Research Products,
Boston, MA), and then detected with 32P-labeled CTR cDNA as
a probe by Southern hybridization. The probe used was
HindIII fragment (2 kb) of rat CTR (C1a) cDNA (generously
provided by Dr. P. Sexton, St. Vincent’s Institute of Medical
Research, Fitzroy, Australia) and labeled using a random primer
DNA labeling kit (Nippon Gene). Hybridization was performed under
stringent conditions at 60°C. For the internal control for RNA
quantity, the same cDNA was amplified using primers specific for rat
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA. A 414-bp
fragment of GAPDH cDNA was amplified using primers
(5'-CATGGAGAAGGCTGGGGCTC-3', nucleotides 306–325, and
5'-AACGGATACATTGGGGGTAG-3', nucleotides 701–720) as described 28 .
PCR products were separated on a 1% agarose gel and stained with
ethidium bromide.
Isolation and culture of macrophages and measurement of the
activity of rat TNF-
Peritoneal macrophages were obtained from Lewis rats by
peritoneal lavage with cold PBS 3 days after i.p. injection of 4.05%
(w/v) thioglycolate broth (Eiken Chemical, Tokyo, Japan) (5 ml/animal).
The cells were washed, resuspended in -MEM containing 10% FCS, and
seeded at 1.2 x 106 in 1 ml/well of 24-well plates.
They were incubated for 16 h to allow macrophages to adhere, and
then nonadherent cells were removed by aspiration. The adherent cells
were used as peritoneal macrophages and stimulated by LPS (1 ng/ml)
(Difco, Detroit, MI) for 2 h. The supernatant was collected and
stored at -80°C. The activity of rat TNF- in supernatants was
assessed by its cytotoxic effect on murine L-929 cells as described
29 . Briefly, L-929 cells were seeded in 96-well plates and cultured
in DMEM containing 5% FCS as monolayer. Actinomycin D (500 ng/ml)
(Sigma, St. Louis, MO) was added with macrophage supernatants, which
were pretreated without or with various concentrations of
anti-murine TNF- Ab and then incubated for 24 h. The
cytotoxic effect was then assessed by staining with amido
black, and the absorbance at 540 nm was read.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-15 enhanced the formation of TRAP-positive MNCs in whole bone
marrow cultures after 3 days of culture. Significant stimulation
(1.8-fold that of control) was seen only in the cultures treated with
high concentrations (100 ng/ml) of IL-15 (Fig. 1
A), and the
stimulation was not detected after longer than 3 days of culture (data
not shown). We next examined the effect of IL-15 on the formation of
POCs induced by htROSCM. IL-15 increased the number of POCs which were
positive for TRAP, a marker of osteoclast, in a dose-dependent manner
(Fig. 1B). Because in this experiment we used purified bone
marrow cells that were completely depleted of stromal cells, the result
demonstrates the enhancing effect that IL-15 exerts in the absence of
stromal cells. Significant stimulation was observed at a concentration
as low as 12.5 ng/ml of IL-15. As shown in Fig. 2, we also found that IL-15 (100 ng/ml)
markedly enhanced the formation of POCs that were positive for Kat1,
another marker for rat osteoclasts 23 , and this response was
neutralized by the addition of graded concentrations of anti-human
IL-15 mAb dose dependently. CTR is a another reliable marker for
osteoclasts. We next examined whether IL-15 increases the number of
POCs that express CTR. IL-15 (100 ng/ml) significantly enhanced the
formation of CTR-positive POCs. Addition of anti-human IL-15 mAb
(200 µg/ml) completely neutralized the stimulatory formation of
CTR-positive POCs by IL-15 (Table I).
Fig. 3A demonstrates
CTR-positive POCs formed in the IL-15-stimulated culture in which a
number of dense grains were seen over the cells. No grains were seen
over the cells when an excess amount of unlabeled sCT was added to the
cells (Fig. 3B). These results demonstrate that IL-15
strongly enhances the formation of POCs, which fulfill several
osteoclastic characteristics in the presence of htROSCM. However, in
the absence of htROSCM, IL-15 alone had no inducing activity on POCs
(data not shown).
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We further examined whether the POCs treated with IL-15 has
increased their ability to form bone-resorbing cells. Nonadherent bone
marrow cells treated with IL-15 (100 ng/ml) were cocultured with
primary osteoblasts to form MNCs, followed by replating onto dentine
slices. As shown in Fig. 4, typical
resorption pits were observed on the dentine surface by scanning
electron microscopy. The resorption area was larger when the culture
was treated with IL-15 (Fig. 4A). Fig. 5 shows a quantitative datum of the
dentine resorption using dentine slices with equal diameters. The
resorption area of the formed MNCs was increased by treatment of the
culture to form POCs with IL-15 before coculture with osteoblasts.
These results demonstrate that the treatment of nonadherent bone marrow
cells with IL-15 produces more resorbing MNCs after coculture with
osteoblasts.
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To investigate whether the stimulatory activity of IL-15 is
correlated with the expression of CTR mRNA, the level of CTR mRNA
expression was analyzed in the cultures treated with graded
concentrations of IL-15. The expression of CTR mRNA was markedly
increased by the treatment of a low concentration (0.1 ng/ml) of IL-15
at maximal level and was not increased by the addition of higher
concentrations of IL-15 (1 and 10 ng/ml) (Fig. 6). In this experiment, the detected band
of CTR mRNA corresponded to the C1a isoform.
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We next examined whether the induction of POCs is required for
IL-15 to enhance activity or whether pretreatment with IL-15 promotes
the formation of POCs by htROSCM. As shown in Fig. 7A, when the bone marrow cells
were pretreated with htROSCM, the subsequent treatment with IL-15
markedly increased the formation of TRAP-positive mononuclear cells.
Conversely, as shown in Fig. 7B, when the bone marrow cells
were pretreated with IL-15 before the addition of htROSCM, the
pretreatment with IL-15 did not have an effect on the formation of
TRAP-positive mononuclear cells. These results suggest that IL-15
amplifies the number of POCs induced by htROSCM, but IL-15 does not
exert its osteoclastogenesis-enhancing activity until POC formation
has initiated.
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,
treatment of the cells with IL-15 (100 ng/ml) for only the first or
second day of culture markedly stimulated the formation of
TRAP-positive mononuclear cells. In contrast, when IL-15 was present in
the culture on only the third or fourth day, no significant stimulation
was observed. These findings show that the enhancing activity of IL-15
is due to its ability to stimulate the early stage but not the late
stage of POC formation.
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and PG are not involved in osteoclastogenesis-enhancing
activity of IL-15
To establish that the enhancing activity of IL-15 on POC formation
is not a secondary effect, we examined the possibility that TNF- and
PG, which stimulate bone resorption, were involved in POC formation
stimulated by IL-15. Neutralizing Ab against murine TNF- abolished
the cytotoxic activity of rat TNF- on L929 cells (Fig. 9A), but it did not abolish
POC formation stimulated by IL-15 even at high concentration (100
µg/ml) (Fig. 9B). In addition, we found that
10-6 M and 10-8 M indomethacin, an inhibitor
of the synthesis of PG, had no suppressive effect on POC formation
enhanced by IL-15 (data not shown). These findings suggest that the
effect of IL-15 is not mediated by TNF- and PG.
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Since IL-15 shares the receptor components ß and c with IL-2,
and c with IL-7, we investigated whether these common receptor
components are involved. We first examined the effect of IL-2 and of
IL-7 on the formation of POCs. As shown in Fig. 10, neither IL-2 nor IL-7 had an effect
on the formation of POCs even at high concentration.
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).
These findings suggest that IL-15 uses some of the components of IL-2R,
ß, or c in POC formation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The activity of IL-15 enhanced the formation of POCs, which occurs at the early stage of osteoclastogenesis, rather than the formation of MNCs. IL-15 increased the number of POCs with osteoclastic phenotypes including TRAP, CTR, and Kat1, a unique osteoclast Ag that we recently isolated 23 . In addition, IL-15 markedly increased the level of CTR mRNA. These results demonstrate that IL-15 is an enhancer of osteoclastogenesis.
IL-15R mRNA is expressed in various types of cells including
macrophages and bone marrow stromal cell lines 6 . In addition,
several cytokines are known to stimulate osteoclastogenesis by
mediating stromal cells 30, 31, 32 . The question was raised whether the
enhancing activity of IL-15 on POC formation might be mediated by other
cytokines secondarily induced. However, we obtained several results
that were contrary to this prediction: 1) IL-15 exerted its activity in
culture completely free of stromal cells and macrophages. This result
indicates that the activity of IL-15 is not mediated by these cells; 2)
although IL-15 is known to strongly stimulate TNF- from NK cells or
macrophages 4, 33, 34 , we confirmed with anti-TNF- Ab that the
effect of IL-15 is not mediated by TNF- produced in the cultures; 3)
some of the stimulation activity on osteoclast generation is dependent
on PG synthesis 35, 36 . We also found that the enhancing activity of
IL-15 does not require synthesis of PG; 4) without htROSCM, IL-15 has
no effects on the development of cells with osteoclastic phenotypes.
IL-15 may interact with some factors in htROSCM. Especially, macrophage
CSF (M-CSF) is one of important factors for osteoclast
differentiation. However, because htROSCM is heated medium, we have
found that the activity of M-CSF in this conditioned medium was
destroyed 21 . We also found that IL-15 did not induce POCs with the
combination of M-CSF, IL-3, and stemcell factor (SCF) (our
unpublished results), suggesting that the effect of IL-15 is not
mediated by these cytokines. Taken together, it is likely that the
enhanced POC formation induced by IL-15 is not attributable to other
cytokines is but caused by direct action.
Surprisingly, IL-15 exerts its strong activity by stimulating cells at the very early stage (only the first 24 or 48 h) of culture. It has previously been reported that IL-15 has an ability to induce differentiation of NK cells from CD34+ hematopoietic progenitor cells 7 . These results suggest that some populations of immature hematopoietic cells are capable of responding to IL-15 and mediate differentiation toward osteoclastogenesis. In addition, we found that IL-15 alone did not have any osteoclastogenesis activity; however, when bone marrow cells were pretreated with htROSCM, the subsequent treatment of these cells with IL-15 markedly enhanced the formation of POCs. These results raise the possibility that the enhancing activity of IL-15 is mediated by the receptor expressed in the osteoclast progenitor cells and preosteoclasts. Very interestingly, an IL-15 concentration as low as 0.1 ng/ml markedly increased the expression level for CTR mRNA, suggesting that the receptor system mediating osteoclastogenesis acts through the high affinity receptor. Such low concentration of IL-15 stimulates the proliferation of T cells 1 in which high affinity IL-15 receptor complex is induced.
Since mRNA of IL-15R and that of IL-2R are coexpressed in
lymphocytes, IL-2 shares many stimulative activities with IL-15 in
these cells. However, the cellular distribution of IL-15R message is
known to be different from that of IL-2R. The inability of IL-2 to
stimulate osteoclast differentiation suggests that some populations of
hematopoietic cells destined to differentiate into osteoclasts express
mRNA for IL-15R but not for IL-2R. However, certain other IL-2R
components seem to be involved in the IL-15 receptor system in
osteoclastogenesis. IL-2 shares receptor components ß and c with
IL-15, while IL-7, a stimulator of B cell and macrophage
differentiation 37, 38 , shares a c chain with IL-15 and IL-2.
Although neither IL-2 nor IL-7 stimulated POC formation, the treatment
of bone marrow cells with IL-7 or IL-2 before the treatment with IL-15
partially abolished the enhancing effect of IL-15. This result suggests
that the IL-15 receptor system in osteoclastogenesis involves the
common component, c. The pretreatment of bone marrow cells with IL-7
or IL-2 probably down-regulates available c molecules and inhibits
the formation of POCs. Recently, a receptor designated as IL-15RX was
found in mast cells 8 . The IL-15RX system in mast cells does not
involve IL-2R, ß, c or IL-15R, and the signal is transduced
by activating JAK-2, unlike the JAK-1/3 used in lymphocytes. In our
preliminary experiments, we found that the enhancement of POC formation
by IL-15 was not abolished by the treatment with the inhibitor of JAK-2
(our unpublished result). This result suggests that the IL-15 receptor
system in osteoclast progenitor cells is different from those of mast
cells. However, further studies are necessary to elucidate the
mechanism of signal transduction of IL-15 in POC formation.
This study provides the first evidence of different biological
activities between IL-15 and IL-2 in osteoclast development. It would
be of interest to investigate what components of the IL-15 receptor
system are used in osteoclast progenitor cells. Previous studies
related to the wide distribution of mRNA for IL-15R and IL-15
suggested that IL-15 had pleiotropic functions in a variety of cells.
Our findings demonstrate one such activity of IL-15 in
osteoclastogenesis and suggest a possible role for IL-15 in the
pathological loss of bone in inflammatory diseases.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Akiko Kukita, Department of Microbiology. Saga Medical School, 5-1-1, Nabeshima, Saga 849-8501, Japan. E-mail address:
3 Abbreviations used in this paper: MNCs, multinucleated osteoclast-like cells; POCs, mononuclear preosteoclast-like cells; CTR, calcitonin receptor; 1,25(OH)2D3, 1,25-dihydroxyvitamin D3; sCT, salmon calcitonin; TRAP, tartrate-resistant acid phosphatase; htROSCM, heat-treated conditioned medium derived from rat osteoblastic cell line ROS17/2.8; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; JAK, Janus kinase; M-CSF, macrophage colony-stimulating factor; SCF, stem cell factor.
Received for publication June 22, 1998. Accepted for publication December 2, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain of the IL-2 receptor. EMBO J. 14:3654.[Medline]
production in rheumatoid arthritis. Nat. Med. 3:189.[Medline]
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