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Department of Biochemistry (N.U., N.T., K.I., Y.U., T.S., T.S.), School of Dentistry, Showa University, Tokyo, 142-8555; Snow Brand Milk Products Company (H.Y., A.M., K.H.), Tochigi, 329-0512, Japan; and St. Vincent’s Institute of Medical Research (M.T.G., T.J.M.), Fitzroy, Victoria 3065, Australia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B ligand (RANKL)/osteoclast differentiation
factor, inhibits both differentiation and function of osteoclasts. We
previously reported that OPG-deficient mice exhibited severe
osteoporosis caused by enhanced osteoclastic bone resorption. In the
present study, potential roles of OPG in osteoclast differentiation
were examined using a mouse coculture system of calvarial osteoblasts
and bone marrow cells prepared from OPG-deficient mice. In the absence
of bone-resorbing factors, no osteoclasts were formed in cocultures of
wild-type (+/+) or heterozygous (+/-) mouse-derived osteoblasts with
bone marrow cells prepared from homozygous (-/-) mice. In contrast,
homozygous (-/-) mouse-derived osteoblasts strongly supported
osteoclast formation in the cocultures with homozygous (-/-) bone
marrow cells, even in the absence of bone-resorbing factors. Addition
of OPG to the cocultures with osteoblasts and bone marrow cells derived
from homozygous (-/-) mice completely inhibited spontaneously
occurring osteoclast formation. Adding 1
,25-dihydroxyvitamin
D3 [1,25(OH)2D3] to these
cocultures significantly enhanced osteoclast differentiation. In
addition, bone-resorbing activity in organ cultures of fetal long bones
derived from homozygous (-/-) mice was markedly increased,
irrespective of the presence and absence of bone-resorbing factors, in
comparison with that from wild-type (+/+) mice. Osteoblasts prepared
from homozygous (-/-), heterozygous (+/-), and wild-type (+/+) mice
constitutively expressed similar levels of RANKL messenger RNA,
which were equally increased by the treatment with
1,25(OH)2D3. When homozygous (-/-)
mouse-derived osteoblasts and hemopoietic cells were cocultured, but
direct contact between them was prevented, no osteoclasts were formed,
even in the presence of 1,25(OH)2D3 and
macrophage colony-stimulating factor. These findings suggest that OPG
produced by osteoblasts/stromal cells is a physiologically important
regulator in osteoclast differentiation and function and that RANKL
expressed by osteoblasts functions as a membrane-associated form. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B (RANK) ligand (RANKL) (2), TNF-related
activation-induced cytokine (TRANCE) (3), and OPG ligand (4), which
were independently identified by other investigators. RANKL induced
osteoclast differentiation from mouse hemopoietic cells and human
peripheral blood mononuclear cells in the presence of macrophage
colony-stimulating factor (M-CSF) (5, 6). Neither osteoblasts/stromal
cells nor osteotropic factors were necessary for osteoclast formation
from spleen cells induced by RANKL and M-CSF (5, 6). In 1997, we purified osteoclastogenesis inhibitory factor (OCIF) from conditioned medium of human embryonic fibroblasts, IMR-90, which had a capability to inhibit osteoclast formation in mouse cocultures of hemopoietic cells and osteoblasts/stromal cells (7). OCIF is a heparin-binding basic glycoprotein, which has been isolated as a monomer with an apparent Mr of 60K and a disulfide-linked homodimer with an Mr of 120K (7). Cloning of its complementary DNA revealed that OCIF is a TNF receptor family member (8, 9), identical to OPG (10) and TNF receptor-like molecule 1 (11, 12). Hepatic expression of OPG in transgenic mice resulted in osteopetrosis (10). OPG inhibited osteoclast formation by directly binding to a ligand for OPG expressed on osteoblasts/stromal cells (8).
We previously reported that not only osteoclast progenitors but also mature osteoclasts strongly expressed messenger RNA (mRNA) of RANK, a receptor for RANKL (13, 14). Like OPG, a soluble form of RANK inhibited osteoclast differentiation and function of mature osteoclasts (13, 14). In addition, polyclonal antibodies against the extracellular domain of RANK induced osteoclast formation in spleen cell cultures, in the presence of M-CSF, because of clustering of the surface receptors (14, 15). These findings indicate that RANK is the signaling receptor essential for RANKL-mediated osteoclastogenesis and that OPG acts as a decoy receptor for RANKL to compete against RANK.
Physiological roles of OPG have been studied in OPG-deficient mice produced by targeted disruption of the gene (16, 17). OPG-deficient mice were viable and fertile, but they exhibited severe osteoporosis caused by enhanced osteoclast formation and function (16, 17). Destruction of growth plates and lack of trabecular bone, with an increase in the number of osteoclasts, were detected in long bones of adult OPG-deficient mice. The strength and mineral density of their bones were markedly reduced. These findings demonstrate that OPG is a key factor acting as a negative regulator against osteoclastogenesis and bone resorption in vivo. To elucidate the potential roles of OPG produced by osteoblasts in osteoclast differentiation and function, we examined osteoclast formation in a mouse coculture system and bone-resorbing activity in a long-bone organ culture system using the wild-type and OPG-deficient mice. The supporting activity of osteoblasts, to induce osteoclast formation in cocultures, was significantly increased when OPG-deficient mouse-derived osteoblasts were used. In addition, bone-resorption in organ cultures of fetal long bones obtained from OPG-deficient mice was markedly increased.
Because RANKL is a type II transmembrane protein, this cytokine seems
to support osteoclast formation as a membrane-associated factor.
However, recent reports indicate another possibility: that RANKL also
acts as a soluble form to induce osteoclast formation. Lum et
al. (18) reported that RANKL was released form cells by shedding
with a TNF-converting enzyme (TACE). Kong et al. (19)
also showed that activated murine T lymphocytes secreted an active form
of RANKL into culture medium. These findings indicate the possibility
that RANKL produced by osteoblasts/stromal cells may be neutralized by
OPG simultaneously produced by osteoblasts/stromal cells. Using
OPG-deficient mice, we show here that RANKL expressed by osteoblasts
functions as a membrane-associated form.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Drugs
Bacterial collagenase and 1,25-dihydroxyvitamin
D3 (1,25(OH)2D3) were obtained
from Wako Pure Chemical Industries, Ltd. (Osaka, Japan).
Recombinant human M-CSF (Leukoprol) was obtained from Yoshitomi
Pharmaceutical Company (Osaka, Japan). Human PTH (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) was obtained
from Peptide Institute (Osaka, Japan). Recombinant human
OPG and soluble form of mouse RANKL (sRANKL) were prepared as described
previously (1, 8). Type I collagen gel solution (Cell matrix Type-IA)
was obtained from Nitta Gelatin, Inc. (Osaka, Japan).
125I-labeled human calcitonin and
45CaCl2 were obtained from Amersham Pharmacia Biotech (Buckinghamshire, UK). Other chemicals and
reagents used were of analytical grade.
Mouse coculture system for osteoclastogenesis
To isolate primary osteoblasts from either OPG-deficient or
wild-type mice, calvaria from 2-day-old mice were cut into small pieces
and cultured for 5 days in collagen-gel prepared in -MEM containing
10% FBS (JRH Biosciences, Lenexa, KS) (20, 21, 22).
Osteoblasts grown from the calvarium were collected by treatment of
collagen gel cultures with collagenase, and they were stored at -80 C
until use. Osteoblasts (104 cells/well) prepared
from each mouse were coculture, for 7 days, with bone marrow cells
(1.5 x 105 cells/well) obtained from
OPG-deficient mice, in a 48-well plate with 0.3 ml of -MEM
containing 10% FBS, in the presence or absence of
10-8 M
1,25(OH)2D3. In some experiments, bone
marrow cells (3 x105 cells) prepared from homozygous
(-/-) and wild-type (+/+) adult mice (11-week-old males) were
cultured in the presence of sRANKL (100 ng/ml) and M-CSF (50 ng/ml) for
5 days (1). The culture medium was changed every 3 days. Adherent cells
were then fixed with 10% formaldehyde in PBS, treated with
ethanol-acetone (50:50), and stained for tartrate-resistant acid
phosphatase (TRAP), as described previously (23). TRAP-positive
multinucleated cells containing more than three nuclei were counted as
osteoclasts. Expression of calcitonin receptors was assessed by
autoradiography using 125I-labeled human
calcitonin (23).
Fetal long-bone organ culture system
Bone-resorbing activity was measured using a modification of
Raisz’s organ culture method (24). In short, pregnant OPG heterozygous
(+/-) mice were injected sc with 25 µCi of
45Ca on day 16 of gestation. Twenty-four hours
after injection, shafts of radii and ulnae were dissected from fetuses,
cleaned free of surrounding muscle and fibrous tissues, and precultured
in serum- or BSA-free BGJb medium (Life Technologies,
Grand Island, NY). After preincubation for 48 h, the bones were
transferred into 0.5 ml BGJb medium containing 0.2% BSA and incubated
for 72 h in the presence or absence of test materials.
Bone-resorbing activity was expressed as the percent release of
45Ca from prelabeled bones, as described
previously (24).
PCR amplification of reverse-transcribed mRNA
For semiquantitative RT-PCR analysis, total cellular RNA was
extracted from calvarial osteoblasts treated, with or without
10-8 M
1,25(OH)2D3, for 48 h using Trizol
solution (Life Technologies). First-strand complementary
DNA was synthesized from total RNA with random primers and was
subjected to PCR amplification with EX Taq polymerase
(Takara Biochemicals, Shiga, Japan) using specific PCR primers: mouse
RANKL, 5'-CGCTCTGTTCCTGTACTTTCGAGCG-3' (forward, nucleotides 195–219)
and 5'-TCGTGCTCCCTCCTTTCATCAGGTT-3' (reverse, nucleotides 757–781);
mouse glyceraldehyde-3-phosphate dehydrogenase (GAPDH),
5'-ACCACAGTCCATGCCATCAC-3' (forward, nucleotides 566–585) and
5'-TCCACCACC-CTGT- TGCTGTA-3' (reverse, nucleotides 998-1017).
Preliminary experiments were performed to ensure that the number of PCR
cycles was within the exponential phase of the amplification curve. PCR
products were resolved on a 2% agarose gel, and the reaction was
confirmed by Southern blot transfer onto nylon membranes (Hybond-N;
Amersham Pharmacia Biotech) and hybridization with
32P-labeled internal sense oligonucleotide
probes; mouse RANKL,
5'-GAGCCTCAGGCTTGCCCCGCCGGGCCACATCGA-GCCACGAACCTTCCATCATAGCT GGAA-3'
(forward, nucleotides 419–479); mouse GAPDH,
5'-GGGGCAGCCCAGAACATCATCCCTGCATCCACTGGTGCTGC
CAAGGC-TGTGGGCAAGGTC-3' (forward, nucleotides 641–700).
Statistical analysis
The data were analyzed by one-factor ANOVA and Student’s
t test (Stat View; Abacus Concepts Inc., Berkeley, CA). The
Student’s t test was performed when the ANOVA test
indicated significance at the P < 0.0001 level. All values
were represented as the means ± SEM of
quadruplicate cultures.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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; A-a, A-b, and B). In contrast,
homozygous (-/-) mouse-derived osteoblasts strongly supported
formation of TRAP-positive mononuclear and multinucleated cells, which
appeared as dark red cells in the coculture, even in the
absence of bone-resorbing factors (Fig. 1, A-c and B). An
autoradiographic study, using labeled calcitonin, revealed that
TRAP-positive cells formed in these cocultures possessed calcitonin
receptors (data not shown). Addition of OPG (10 ng/ml) to the
cocultures of osteoblasts and bone marrow cells derived from homozygous
(-/-) mouse completely inhibited the spontaneously occurring
differentiation of TRAP-positive osteoclasts (Fig. 1A-d). Treatment of
these cocultures with 1,25(OH)2D3
(10-8
M) significantly enhanced osteoclast formation in
all cocultures (Fig. 1B).
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). In
addition, PTH (10-6
M) markedly stimulated 45Ca release
from homozygous (-/-) bone, which was much higher than that from
wild-type (+/+) bone treated with PTH (Fig. 2). Similarly,
bone-resorbing activity induced by
1,25(OH)2D3
(10-8 M) in
homozygous (-/-) (n = 2) mice was significantly higher than that
in wild-type (+/+) mice (n = 4) (73.2 ± 4.7% vs.
26.4 ± 8.9%, P < 0.01). OPG (1000 ng/ml) almost
completely inhibited 45Ca release induced by PTH
(10-6
M) in organ cultures of OPG-deficient bone, as
well as in heterozygous (+/-) and wild-type (+/+) bone (Fig. 2).
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,25(OH)2D3 for 3 days (Fig. 3).
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Recent studies have shown that RANKL may act as a soluble factor for
inducing osteoclast formation in vitro. To address this
issue, we examined whether osteoblasts produce a soluble form of RANKL,
using OPG-deficient mice because the inhibitory effects elicited by OPG
are eliminated. Osteoblasts obtained from homozygous (-/-) mice were
spot-cultured for 2 h in the left side of a single culture dish,
then mouse bone marrow cells also obtained from homozygous (-/-) mice
were uniformly plated over the culture dish. When the spot coculture
was treated with 1,25(OH)2D3
(10-8
M) and M-CSF (50 ng/ml) for 7 days, TRAP-positive
osteoclasts were formed exclusively inside the colony of osteoblasts
(Fig. 4, A and B). Addition of sRANKL
(100 ng/ml) and M-CSF (50 ng/ml) to the spot coculture stimulated
osteoclast formation both inside and outside the colony (Fig. 4C).
These findings suggest that membrane- or matrix-associated RANKL is
important for osteoclast differentiation induced by
osteoblasts.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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OPG has been shown to be ubiquitously expressed in many tissues (8, 10, 12). It was also reported that the serum concentration of OPG is
increased in postmenopausal women who have a high rate of bone turnover
(30). In the present study, the lack of OPG production by osteoblasts
stimulated osteoclast formation in cocultures of osteoblasts and bone
marrow cells. Bone-resorbing activity was also elevated in
OPG-deficient long bones in the presence and absence of bone-resorbing
factors. The enhanced osteoclastogenesis and bone resorption in
vitro in OPG-deficient mice were completely inhibited by adding
OPG. The OPG deficiency did not affect the levels of RANKL mRNA, which
was constitutively expressed by osteoblasts from wild-type (+/+),
heterozygous (+/-), and OPG-deficient (-/-) mice at an equivalent
level. Furthermore, RANKL mRNA levels in osteoblasts were similarly
up-regulated by the treatment with
1,25(OH)2D3 in each of the three OPG genetic
backgrounds. Consistent with the present findings, anti-OPG
antibody enhanced osteoclast formation induced by
1,25(OH)2D3 in mouse bone marrow cultures
(12). These findings indicate that, besides RANKL and M-CSF, OPG
produced by osteoblasts is also a physiologically important regulator
of osteoclast formation and function of mature osteoclasts.
OPG gene expression in osteoblasts/stromal cells is down-regulated by
1,25(OH)2D3 and dexamethasone (8, 31), and
the combination of these agents is known to support osteoclastogenesis
in the coculture system. In contrast, transforming growth factor-ß
inhibits osteoclast formation in mouse cocultures, and this factor
induces OPG production by osteoblasts or bone marrow stromal cells
(ST2) (32, 33). These observations raise the possibility that
osteoclast differentiation is critically regulated by OPG, which is
produced as a local factor by osteoblasts/stromal cells in response to
osteotropic factors or cytokines. Additionally, we reported that the
concentration of OPG in synovial fluids was significantly lower in
patients with rheumatoid arthritis than patients with gout (34),
suggesting a potential role of OPG in the protection from accelerated
osteoclastic bone resorption.
Recently, Kong et al. (19) and our group (35) independently reported that activated T cells supported osteoclast differentiation via RANKL-RANK interaction. Kong et al. (19) also reported that, unlike osteoblasts/stromal cells, activated T lymphocytes seemed to secrete a soluble form of RANKL into culture medium, which induced osteoclastogenesis in vitro. This suggests that there is a difference between osteoblasts/stromal cells and T lymphocytes in the mode of RANKL production. Osteoblasts/stromal cells express RANKL as a membrane-bound or matrix-associated form to promote differentiation of osteoclast progenitors into osteoclasts through a mechanism involving cell-to-cell contact. Elaboration of a soluble form of RANKL may be the result of processing the mature protein by TACE or a TACE-like enzyme (18). Furthermore, it has been reported that osteoclasts are formed when hemopoietic cells are cocultured with activated T cells fixed with paraformaldehyde (19). This indicates that membrane-bound RANKL is also important for the activated T-cell-mediated bone destruction.
Under physiological conditions, osteoclast formation requires cell-to-cell contact with osteoblasts/stromal cells, which generate RANKL as a membrane-bound factor in response to several bone resorbing factors. In normal bone remodeling, osteoblastic bone formation always occurs as a programmed manner accurately and quantitatively just after osteoclastic bone resorption. In contrast, in pathological bone resorption, as in rheumatoid arthritis, T cells seem to secrete a soluble form of RANKL, which acts directly on osteoclast progenitors without cell-to-cell contact. Thus, it is attractive to consider that cell-to-cell contact between osteoclast progenitors and osteoblasts/stromal cells may leave some memory for bone formation in osteoblasts/stromal cells. This possibility is currently being explored in our laboratory.
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Acknowledgments |
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Footnotes |
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1 This work was supported, in part, by a grant-in-aid (11470393) and
the High-Technology Research Center Project from the Ministry of
Education, Science, Sport and Culture of Japan. 
Received February 22, 2000.
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References |
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(TNF-)-converting enzyme-like
protease in shedding of TRANCE, a TNF family member involved in
osteoclastogenesis and dendritic cell survival. J Biol Chem 274:13613–13618,25-dihydroxyvitamin D3 in osteoclast
differentiation and function. Methods Enzymol 282:223–235[Medline]
,25-dihydroxyvitamin D3,
prostaglandin E2, or parathyroid hormone in the
microenvironment of bone. Biochem Biophys Res Commun 246:337–341[CrossRef][Medline]
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