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Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin-deficient mice.

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THE ANATOMICAL RECORD 266:218 –225 (2002)
DOI 10.1002/ar.10061
Osteoclast Induction in Periodontal
Tissue During Experimental
Movement of Incisors in
Osteoprotegerin-Deficient Mice
TAKAHIRO OSHIRO,1,2 AYA SHIOTANI,1,2 YOSHINOBU SHIBASAKI,1
2
AND TAKAHISA SASAKI *
1
Department of Orthodontics, School of Dentistry, Showa University, Tokyo, Japan
2
Department of Oral Histology, School of Dentistry, Showa University, Tokyo, Japan
ABSTRACT
Osteoprotegerin (OPG) is a novel secreted member of the tumor necrosis factor (TNF)
receptor superfamily that negatively regulates osteoclastogenesis. The receptor activator of
the NFKB ligand (RANKL) is one of the key regulatory molecules in osteoclast formation and
binds to OPG. In this study, it was suggested that OPG and RANKL are involved in alveolar
bone remodeling during orthodontic tooth movement. We examined RANKL localization and
osteoclast induction in periodontal tissues during experimental movement of incisors in
OPG-deficient mice. To produce orthodontic force, an elastic band was inserted between the
upper right and left incisors for 2 or 5 days, and the dissected maxillae were examined for
cytochemical and immunocytochemical localization of tartrate-resistant acid phosphatase
(TRAP), vacuolar-type H⫹-ATPase, and RANKL. Compared to wild-type OPG (⫹/⫹) littermates, TRAP-positive multinucleated cells were markedly induced in the periodontal ligament (PDL) on the compressed side and in the adjacent alveolar bone of OPG-deficient mice.
These multinucleated cells exhibited intense vacuolar-type H⫹-ATPase along the ruffled
border membranes. Because of accelerated osteoclastic resorption in OPG-deficient mice,
alveolar bone was severely destroyed and partially perforated at 2 and 5 days after force
application. In both wild-type and OPG-deficient mice, RANKL expression became stronger
at 2 and 5 days after force application than before force application. There was no apparent
difference in intensity of RANKL expression between OPG (⫹/⫹) littermates and OPGdeficient mice. In both wild-type and OPG-deficient mice, expression of RANKL protein was
detected in osteoblasts, fibroblasts, and osteoclasts mostly located in resorption lacunae.
These results suggest that during orthodontic tooth movement, RANKL and OPG in the
periodontal tissues are important determinants regulating balanced alveolar bone
resorption. Anat Rec 266:218 –225, 2002. © 2002 Wiley-Liss, Inc.
Key words: osteoprotegerin-deficient mice; osteoprotegerin; receptor activator of NFKB ligand; osteoclast; periodontal tissue; tooth movement
Orthodontic tooth movement is mediated by the coupling of bone resorption on the compressed side of the
periodontal ligament (PDL) and bone formation on the
stretched side of the PDL (Yokoya et al., 1997; Chung et
al., 1999; Sato et al., 2000a, b). Differentiation and cellular
activities of both osteoblasts and osteoclasts are highly
regulated by a wide variety of osteotropic hormones, inflammatory mediators, and growth factors (Suda et al.,
1992). An imbalance of the cell functions of osteoblasts
and osteoclasts, therefore, results in skeletal abnormalities such as osteopetrosis, osteoporosis, and Paget’s disease (Osier and Marks, 1992; Roodman, 1992).
©
2002 WILEY-LISS, INC.
During bone remodeling, the differentiation, maturation, and function of osteoclasts are regulated by osteoblast-derived factors. One of these, osteoprotegerin (OPG),
is a novel secreted member of the tumor necrosis factor
*Correspondence to: Takahisa Sasaki, Department of Oral Histology, School of Dentistry, Showa University, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan. Fax: ⫹81-3-3781-0255.
E-mail: oralhist@dent.showa-u.ac.jp
Received 7 August 2001; Accepted 28 December 2001
Published online 00 Month 2002
219
PERIODONTAL TISSUE IN OPG (–/–) MICE
(TNF) receptor superfamily that negatively regulates osteoclastogenesis (Simonet et al., 1997; Tsuda et al., 1997;
Yasuda et al., 1998a, b). OPG appears to locally and/or
systemically inhibit the differentiation of osteoclast precursors into mature osteoclasts, by interrupting the osteoblast– osteoclast precursor interaction (Simonet et al.,
1997; Akatsu et al., 1998; Yasuda et al., 1998a, b). OPG
also inhibits in vitro osteoclastogenesis elicited through
distinct signaling pathways stimulated by 1,25(OH)2D3,
PTH, or IL-11 (Simonet et al., 1997; Tsuda et al., 1997;
Matsuzaki et al., 1998; Yasuda et al., 1998a). Therefore,
OPG inhibits ovariectomy-induced bone loss in rats (Bateman et al., 2000). In contrast, OPG deficiency results in
severe osteoporosis in both humans and experimental animals (Bucay et al., 1998; Mizuno et al., 1998; Yano et al.,
1999).
Another osteoblast-derived factor, the receptor activator
of the NFkB ligand (RANKL), has been identified as a
member of the membrane-associated TNF ligand family
and an important regulatory molecule of osteoclastogenesis (Lacey et al., 1998; Yasuda et al., 1998b; Matsuzaki et
al., 1998; Tsukii et al., 1998; Fuller et al., 1998; Jimi et al.,
1999; Takami et al., 1999; Udagawa et al., 1999). RANKL
was found to induce osteoclast differentiation from hemopoietic precursors and stimulate their bone resorptive activity (Lacey et al., 1998; Matsuzaki et al., 1998; Yasuda et
al., 1998b; Tsukii et al., 1998; Fuller et al., 1998; Jimi et
al., 1999; Takami et al., 1999; Udagawa et al., 1999).
RANKL is a ligand of OPG and is expressed on the plasma
membrane of osteoblasts/stromal cells (Lacey et al., 1998;
Tsukii et al., 1998; Yasuda et al., 1998a, b). OPG is a
soluble decoy receptor for RANKL, and its inhibition of
osteoclast differentiation is due to direct binding to a
ligand for OPG expressed on osteoblasts/stromal cells
(Matsuzaki et al., 1998; Yasuda et al., 1998a, b; Udagawa
et al., 1999, 2000). The resorptive activity of osteoclasts
induced by soluble RANKL or osteoblasts is completely
inhibited by the simultaneous addition of soluble OPG
(Udagawa et al., 1999). Therefore, osteoclast differentiation and function are thought to be regulated by the counterbalancing influences of RANKL and OPG.
We recently localized RANKL expression in PDL tissue
during orthodontic tooth movement (Shiotani et al., 2001).
However, the involvement of RANKL and OPG in PDL
tissue during orthodontic tooth movement has not yet
been examined. In that regard, OPG-deficient mice provide a useful animal model for osteoporosis without other
abnormalities (Bucay et al., 1998; Mizuno et al., 1998).
From this study of OPG-deficient mice, we report immunocytochemical evidence suggesting that OPG is an important negative regulator of osteoclast induction in periodontal tissues during experimental movement of incisors.
MATERIALS AND METHODS
Animal Use Protocol and Experiments
Throughout the experiments, the animals were maintained following the principles of laboratory animal care
established by the NIH. The animal use protocol was
reviewed, and all experiments were conducted according
to the animal experimental guide approved by the Animal
Experiment Committee, Showa University.
Eight-week-old OCIF/JcL OPG (–/–) mice and their
wild-type OPG (⫹/⫹) littermates (Saitama Experimental
Animals Supply Co. Ltd., Saitama, Japan) (Mizuno et al.,
1998) were used in the experiment. An elastic band (a
stretched piece of rubber) was set between the right and
left incisors in the maxilla of OPG-deficient and wild-type
mice for 2 or 5 days. To maintain the elastic band between
the incisors, both of its ends were fixed with resin. As
baseline controls, both wild-type and OPG-deficient mice
before elastic band insertion were used as day 0 specimens. After tooth movement, and after the mice were
killed with an overdose with ethyl ether anesthesia, the
mice were fixed by intracardiac perfusion with either a
mixture of 4% formaldehyde and 0.1% glutaraldehyde in
0.M sodium cacodylate buffer (pH 7.3) for immunohistochemistry, or 2.5% glutaraldehyde in the same buffer for
ultrastructural observation. The dissected maxillae, including incisors, were decalcified in 10% EDTA solution
for 4 weeks.
Histological, Cytochemical, and
Immunohistochemical Examinations
Decalcified bone tissues were routinely embedded in
paraffin. Sections were stained with hematoxylin and eosin. The other sections were stained for tartrate-resistant
acid phosphatase (TRAP) as described previously (Udagawa et al., 1999, 2000) and examined with an Olympus
VANOX light microscope (Tokyo, Japan).
Other decalcified bone tissues were embedded in LR
white resin (London Resin, Basingstoke, UK), which was
polymerized at –20°C under ultraviolet rays. Ultrathin
sections mounted on Formvar-coated nickel grids were
first treated with 10% bovine serum albumin (BSA) in 0.01
M phosphate-buffered saline (PBS) for 1 hr to block nonspecific binding of antibody. The sections were then incubated with rabbit antiserum raised against either RANKL
(donated by Dr. M. Gillespie, St. Vincent’s Institute of
Medical Research, Victoria, Australia) (Kartsogiannis et
al., 1999) diluted 1:100 with 1% BSA/PBS or vacuolar-type
H⫹-ATPase (donated by Dr. Moriyama, Hiroshima University, Hiroshima, Japan) diluted 1:500 with 1% BSA/
PBS, overnight at 4°C. After incubation, the sections were
rinsed with PBS and incubated with goat anti-rabbit IgG,
conjugated with 10 nm colloidal gold particles (BioCell
Research Laboratories, Cardiff, UK) diluted 1:100 with
PBS for 1 hr at room temperature. After rinsing with PBS
and distilled water, the sections were stained with 2%
uranyl acetate. For light microscopy, decalcified bone tissues were embedded in paraffin, and sections were processed for RANKL localization by the biotin-streptavidinhorseradish peroxidase method, using a Histofine SAB-PO
kit (Nichirei Co. Ltd., Tokyo, Japan). The sections were
incubated for 2 hr with the primary antibody at room
temperature.
RESULTS
In our previous experiment (Yokoya et al., 1997) on
movement of rat molars induced by elastic band insertion,
we showed that the number of osteoclasts steadily increased on the compressed side of the PDL from 1 to 7 days
after force application. At 4 days after elastic band insertion, many osteoclasts, which were immunostained for
vacuolar-type H⫹-ATPase, appeared along the alveolar
bone surfaces on the compressed side of the PDL (Yokoya
et al., 1997). We therefore examined PDL tissues on the
compressed side on days 0, 2, and 5 after elastic band
insertion in both wild-type and OPG-deficient mice.
In wild-type mice, the alveolar bone surfaces facing the
compressed side of the PDL on both days 0 and 2 were very
220
OSHIRO ET AL.
smooth and osteoclasts were seldom observed (Fig. 1a and
b). The mean number of osteoclasts per unit length (1 mm)
of alveolar bone surfaces at the compressed side was only
1.15 ⫾ 1.62 (SD) on day 0, and 3.55 ⫾ 1.95 (SD) on day 2.
On day 5, osteoclasts were increased in number (8.62 ⫾
3.24) along the alveolar bone surfaces (Fig. 1c). On the
other hand, in OPG-deficient mice, even on day 0, many
osteoclasts (5.76 ⫾ 1.49) were already observed not only
along the alveolar bone surfaces but also within wide
vascular canals of bone (Fig. 2a). On day 2, the osteoclast
number increased to 8.20 ⫾ 1.95 (SD), and due to accelerated osteoclastic bone resorption alveolar bone structures were markedly destroyed, exhibiting irregular bone
surfaces and enlarged vascular canals and medullary cavities (Fig. 2b). On day 5, the osteoclast number further
increased to 10.66 ⫾ 5.70 (SD). Although osteoclastic resorption was less prominent than on day 2, alveolar bone
had become very thin, and in some cases completely perforated by PDL tissue (Fig. 2c). Thus, osteoclasts in OPGdeficient mice on days 0, 2, and 5 appeared to be markedly
increased compared to those in wild-type mice.
We then examined the cytochemical characteristics of
these osteoclasts. In both wild-type and OPG-deficient
mice, osteoclasts located along the alveolar bone surfaces
were strongly stained for TRAP (Fig. 3). Ultrastructurally,
these osteoclasts exhibited well-developed ruffled borders,
consisting of deep and regular membrane infoldings toward the cytoplasm, and accumulation of many pale vacuoles in the cytoplasm proximal to the ruffled borders (Fig.
4). Immunoelectron microscopic localization of vacuolartype H⫹-ATPase demonstrated deposition of many immunogold particles, mainly along the limiting membranes of
pale vacuoles and along the ruffled border membranes of
these osteoclasts (Fig. 4).
We further examined RANKL expression in the PDL on
the compressed side in both wild-type and OPG-deficient
mice. RANKL expression was hardly observed in the PDL
on day 0 in wild-type mice (Fig. 5a). However, on day 2,
RANKL immunostaining was clearly observed in osteoblasts facing the alveolar bone surfaces and in some PDL
fibroblasts (Fig. 5b). On day 5, in addition to osteoblasts
and PDL fibroblasts, RANKL immunostaining was observed in multinucleated osteoclasts located in the resorption lacunae of alveolar bone (Fig. 5c). On the other hand,
in OPG-deficient mice, even on day 0, RANKL expression
was detected in osteoblasts facing the alveolar bone surfaces and in some PDL fibroblasts (Fig. 6a). On both days
2 and 5, RANKL immunostaining was clearly observed in
osteoblasts facing the alveolar bone surfaces, PDL fibroblasts, and multinucleated osteoclasts (Fig. 6b and c).
There was no apparent difference in the intensity of
RANKL immunostaining between wild-type and OPG-deficient mice on days 2 and 5 (Figs. 5b and c, and 6b and c).
In immunoelectron microscopic examination of both
wild-type and OPG-deficient mice, deposition of immunogold particles for RANKL localization was mainly observed in the cytoplasm and cisterns of the rough-surfaced
endoplasmic reticulum (RER) of osteoblasts (Fig. 7). Some
immunogold particles were observed along the plasma
membrane of these osteoblasts/stromal cells. Similar subcellular localization of RANKL was also observed in PDL
fibroblasts (data not shown). RANKL localization in osteoclasts was detected as deposition of immunogold particles
in the cytoplasm and along the ruffled border membranes
(Fig. 8). In these immunocytochemical examinations, neg-
ative control sections showed that replacement of the primary antibody with nonimmune normal rabbit serum resulted in sparse immunoreaction throughout the tissue
sections (data not shown).
DISCUSSION
This study showed that, in OPG-deficient mice, OPG
and RANKL in the periodontal tissue are involved in
alveolar bone remodeling during experimental tooth
movement. OPG, RANK, and their ligand, RANKL, coordinate in regulating bone density and structure by the
well-balanced modulation of osteoclast differentiation
from hematopoietic precursors. The soluble form of OPG is
reported to capture and bind their cognate ligand,
RANKL, and prevent these ligands from activating their
target cells, osteoclasts. O’Brien et al. (2001) reported that
recombinant human OPG caused osteoclasts to detach
from the bone surfaces and attach to the adjacent periosteum. OPG transgenic mice show a marked decrease in
mature osteoclasts, but not in the number of osteoclast
precursors (Simonet et al., 1997). These results suggest
that OPG affects the later unknown stage of osteoclast
differentiation. In this regards, Akatsu et al. (1998) reported that OPG inhibited the survival of osteoclasts
formed in mouse marrow cultures in a dose- and timedependent manner, and suggested that OPG affected the
osteoclast number by promoting apoptosis. Murakami et
al. (1998) also reported that apoptosis of osteoclasts was
mediated by up-regulation of OPG, and that this phenomenon was induced by TGF-␤1.
Our results indicate that OPG is a key negative regulator of osteoclastogenesis in PDL tissue during tooth movement. We previously localized RANKL expression in PDL
fibroblasts and osteoblasts on the compressed side of the
PDL (Shiotani et al., 2001). Because cell-to-cell interaction
between osteoblasts/stromal cells and osteoclast precursors is essential for osteoclast formation (Lacey et al.,
1998; Matsuzaki et al., 1998; Tsukii et al., 1998), our
observation suggests that these osteoblasts/stromal cells
and fibroblasts in PDL are involved in supporting osteoclast differentiation during tooth movement. Therefore,
bone remodeling during orthodontic tooth movement is
thought to be regulated by OPG, RANK, and RANKL to
maintain well-balanced alveolar bone structure and bone
mass.
In our results, RANKL expression was increased at 2
and 5 days after force application compared to that on day
0 in both wild-type and OPG-deficient mice. This suggests
that osteoclast differentiation is critically regulated by
RANKL, which is produced as a local factor by osteoblasts/
stromal cells in response to mechanical stress such as
tooth movement, as well as osteotropic factors. Interestingly, except for that on day 0, there was no difference in
the intensity of RANKL expression between wild-type and
OPG-deficient mice. Consistent with our results, Udagawa et al. (2000) reported that OPG deficiency did not
affect RANKL mRNA levels expressed by osteoblasts from
wild-type, heterozygous, and OPG-deficient mice that
showed an equivalent level. In addition, RANKL mRNA
levels in osteoblasts were similarly up-regulated by treatment with 1,25(OH)2D3 in each of the three OPG genetic
backgrounds (Udagawa et al., 2000). RANKL expression
on day 0 in OPG-deficient mice may be closely related to
osteoclast induction.
PERIODONTAL TISSUE IN OPG (–/–) MICE
Fig. 1. a– c: Light micrographs of PDL tissue on the compressed side
in wild-type mice on days (a) 0, (b) 2, and (c) 5 after force application. A
few osteoclasts (arrowheads) are seen in the PDL proper on day 5. AB:
alveolar bone, PDL: periodontal ligament, De: dentine. ⫻330.
Fig. 2. a– c: Light micrographs of PDL tissue on the compressed side
221
in OPG-deficient mice on days (a) 0, (b) 2, and (c) 5 after force application. Osteoclasts (arrowheads) are seen in the PDL proper and within
alveolar bone on days 0, 2, and 5. On days 2 and 5, alveolar bone is
prominently perforated. AB: alveolar bone, PDL: periodontal ligament,
De: dentine. ⫻330.
222
OSHIRO ET AL.
Fig. 3. Intense TRAP staining of osteoclasts (arrowheads) in an OPG-deficient mouse on day 2. AB:
alveolar bone. ⫻330.
Fig. 4. Immunoelectron micrograph of vacuolar-type H⫹-ATPase in an osteoclast in an OPG-deficient
mouse on day 2. Immunogold particles are deposited along the ruffled border membranes. ⫻37,500.
OPG was found in the conditioned medium of human
embryonic lung fibroblasts, 1MR-90 (Tsuda et al., 1997).
In addition, mRNA of the TNF receptor, TR1 (identical to
OPG), was abundantly expressed in primary osteoclasts,
osteogenic sarcoma cell lines, and primary fibroblasts
(Kwon et al., 1998). Transforming growth factor (TGF)-␤1
increased OPG mRNA level and the secretion of OPG
protein in primary osteoblasts and osteoblastic MC3T3-1
and ST2 cell lines (Murakami et al., 1998; Takai et al.,
1998). TGF-␤1 markedly increased the steady-state OPG
mRNA level in a dose-dependent manner, but suppressed
RANKL mRNA expression and inhibited the formation of
TRAP-positive osteoclast-like cells in the presence of
1,25(OH)2D3 (Takai et al., 1998). In this regards, expression of TGF-␤1 mRNA and protein was increased in osteoblasts on the stretched side of the PDL during experimental tooth movement (Nagai et al., 1999). They also
localized type-II receptors for TGF-␤1 in osteoclasts on the
compressed side of the PDL. These results suggest that: 1)
TGF-␤1 negatively regulates osteoclastogenesis through
OPG induction by osteoblasts/stromal cells, and 2) OPG
and RANKL in the local microenvironment are important
determinants regulating balanced and site-specific osteoclastic bone resorption during orthodontic tooth movement. In other words, during tooth movement, stimulation
of osteoclastic bone resorption on the compressed side of
the PDL and inhibition of resorption on the stretched side
are thought to be regulated by RANKL and OPG, respectively. Osteoblasts/stromal cells in the PDL tissue are
thought to play important regulatory roles to cause sitespecific bone resorption in orthodontic tooth movement.
It is also interesting that RANKL is expressed in osteoclasts, particularly in the ruffled border membranes. Because RANKL mRNA was detected in osteoclasts (Kartsogiannis et al., 1999), RANKL is thought to be produced in
osteoclasts rather than by osteoclastic incorporation of
soluble RANKL proteins, which are secreted by osteoblasts/stromal cells in a paracrine manner. Our ultrastructural localization of RANKL in osteoclasts suggests
that RANKL has regulatory function(s) associated with
resorptive function at the ruffled border membranes. In
association with these observations, RANKL was reported
to induce increased pseudopodial motility, associated with
increased cell spreading in osteoclasts, and to stimulate
resorption lacuna formation on cocultured bone slices
(Fuller et al., 1998). In addition, soluble RANKL was
reported to prolong the survival of cultured osteoclasts in
a dose-dependent manner and enhance their resorptive
activity in cocultured dentine slices (Fuller et al., 1998;
Udagawa et al., 1999; Jimi et al., 1999). It can be concluded from these results that, in addition to the regulation of osteoclastogenesis by osteoblastic RANKL, RANKL
PERIODONTAL TISSUE IN OPG (–/–) MICE
Fig. 5. a– c: RANKL immunostaining in PDL tissue on the compressed side in wild-type mice on days (a) 0, (b) 2, and (c) 5 after force
application. RANKL is expressed in osteoblasts, fibroblasts, and osteoclasts. AB: alveolar bone, PDL: periodontal ligament, De: dentine.
⫻330.
223
Fig. 6. a– c: RANKL immunostaining in PDL tissue on the compressed side in OPG-deficient mice on days (a) 0, (b) 2, and (c) 5 after
force application. RANKL is expressed in osteoblasts, fibroblasts, and
osteoclasts. AB: alveolar bone, PDL: periodontal ligament, De: dentine.
⫻330.
224
OSHIRO ET AL.
Fig. 7. Immunoelectron micrograph showing RANKL localization in an osteoblast. Immunogold particle
deposition is seen in RER cisterns and throughout the cytoplasm. ⫻37,500.
Fig. 8. Immunoelectron micrographs showing RANKL localization in osteoclasts. Immunogold particles
are deposited in the ruffled border. ⫻37,500.
PERIODONTAL TISSUE IN OPG (–/–) MICE
expressed in osteoclasts may have self-regulatory roles in
their resorptive activity and survival.
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