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Denervation Resulting in Dento-Alveolar Ankylosis Associated with Decreased Malassez Epithelium

K. Fujiyama, T. Yamashiro, T. Fukunaga, T.A. Balam, L. Zheng and T. Takano-Yamamoto
J DENT RES 2004 83: 625
DOI: 10.1177/154405910408300808

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 RESEARCH REPORTS
Biological
K. Fujiyama, T. Yamashiro,
T. Fukunaga, T.A. Balam,
L. Zheng, and T. Takano-Yamamoto*
Department of Orthodontics and Dentofacial Orthopedics,
Graduate School of Medicine and Dentistry, Okayama
University, 2-5-1 Shikata-cho, Okayama 700-8525, Japan;
*corresponding author, t_yamamo@md.okayama-u.ac.jp
J Dent Res 83(8):625-629, 2004
ABSTRACT
Inferior alveolar nerve denervation causes
appreciable decreases in the distribution of
epithelial rests of Malassez. To explore roles of
the Malassez epithelium, we attempted to evaluate
possible changes in dento-alveolar tissues
surrounding this epithelium by experimental
denervation. We found that denervation led to
dento-alveolar ankylosis with a decrease in the
width of the periodontal spaces. Interestingly, with
regeneration of the Malassez epithelium 10 weeks
after the denervation, the periodontal space width
showed a correspondingly significant increase.
These findings suggest that the Malassez
epithelium may be involved in the maintenance of
periodontal space and that sensory innervation
might be indirectly associated with it. In addition,
it is of interest that denervation activated root
resorption of the coronal root surface and that the
consequently resorbed lacunae were repaired by
cellular cementum. It is suggested that Malassez
epithelium may negatively regulate root resorption
and induce acellular cementum formation.
KEY WORDS: epithelial cell rests of Malassez,
ankylosis, cementogenesis.
Received September 13, 2003; Last revision May 14, 2004;
Accepted June 2, 2004
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International and American Associations for Dental Research
Denervation Resulting in
Dento-Alveolar Ankylosis
Associated with Decreased
Malassez Epithelium
INTRODUCTION
T1997).
he periodontal ligament is the unique connective tissue that surrounds the
roots of teeth and connects them with the alveolar bone (Berkovitz et al.,
It is of interest that the width of the periodontal space is maintained
around the whole root surface, but the molecular basis for this is not clear.
Unlike the root surface, alveolar bone is an actively remodeling
compartment and can adapt its shape to accommodate the periodontal space
during root development (Yamashiro et al., 2003) and physiological tooth
movement in the distal direction (Takano-Yamamoto et al., 1994). Hence, it
is likely that putative molecules released at the root surface might be
involved in the maintenance of the periodontal ligaments. On the root
surface, cellular and acellular cementum is present, and the epithelial rests
of Malassez are also located in the periodontal ligament tissue near the root
cementum (Beertsen et al., 2000). Therefore, it may be speculated that the
cementum and/or the epithelium might play an important role in maintaining
the periodontal space.
Previous studies have showed possible roles of this epithelium in
maintenance of the periodontal ligament (Lindskog et al., 1988) and
differentiation of cementoblasts. However, since the epithelial rests of
Malassez are embedded in the periodontal ligament, consequently making it
difficult to isolate and/or manipulate Malassez epithelium both in vitro and
in vivo, no firm evidence has been obtained to support their functional role
(Wesselink and Beertsen, 1993; Ten Cate, 1996).
The periodontal ligament is abundantly innervated by sensory nerves
(Heyeraas et al., 1993; Fristad, 1997), and a previous ultrastructural
observation demonstrated an intimate relationship between sensory nerve
endings and the basal lamina of the epithelial rests of Malassez (Lambrichts
et al., 1993). Malassez epithelium is composed of different cell types, in
common with epithelial tissue from other locations, and includes
neuroendocrine cells containing several neuropeptides (Kvinnsland et al.,
2000). In addition, Malassez epithelium is immunopositive for trkA, a high-
affinity NGF receptor, and denervation of the inferior alveolar nerve results
in a marked decrease in the distribution area and size of the clusters of the
Malassez epithelium (Yamashiro et al., 2000a). These findings indicate that
the sensory nerve could play a regulatory role in maintaining epithelial rests
of Malassez.
To explore the possible functions of the Malassez epithelium, we
evaluated tissue changes around the epithelium after denervation. We found
that denervated rats showed dento-alveolar ankylosis after 6 wks, and we
evaluated the detailed histological changes associated with this process.
MATERIALS & METHODS
Nerve Denervation and Processing of the Tissues
The Animal Committee of the Graduate School of Medicine and Dentistry,
625
626
Figure 1. Sagittal views of the lower first, second, and third molars. The
dento-alveolar ankylosis was indicated in the denervated rats
(arrowhead in B compared with A). (C,D,E,F) Histological appearance
of the first molars in sham (C,E) and denervated rats (D,F). E and F are
higher-magnification views of the periodontal ligament in (C) and (D),
respectively. (F) The dento-alveolar bone ankylosis (*) was evident at the
coronal periodontal regions. (G) A diagram of regions of the
morphometric measurement of first molars. Periodontal space width was
measured between the arrows. (H) The periodontal space width was
measured at 6, 8, and 10 wks after the denervation or sham operation.
Data are shown as mean ± SD (n = 5/group). AB, alveolar bone; PDL,
periodontal ligament; D, dentin. Bar = 500 ␮m. *Significantly different
from the value of the sham rats (P < 0.05). a, significantly different from
the value of the 8w-DN rats (P < 0.05).
Okayama University, approved the experimental procedure. Seven-
week-old male Wistar rats were used for this study. Denervated
rats were prepared by inferior alveolar nerve transection, as
described previously (Wakisaka et al., 1985; Yamashiro et al.,
2000a,b). The right inferior alveolar nerve was transected, while
the left nerve was also exposed, but not transected, in a sham
operation (Sham). Six, 8, or 10 wks after the denervation, the
mandibular alveolar bones were excised, post-fixed, and
decalcified, as described previously (Yamashiro et al., 2000a,b).
For immunohistochemistry with TrkA antibody, horizontal
sections 50 ␮m thick were cut serially on a cryostat (Sakura,
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International and American Associations for Dental Research
Fujiyama et al. J Dent Res 83(8) 2004
Tokyo, Japan). For histological observation and histometric
analysis, 7-␮m-thick paraffin-embedded sections were also cut on
a microtome (Leica, Oberkochen, Germany).
Immunohistochemistry for TrkA
and Staining for TRAP Activity
TrkA was used as a marker for epithelial cells, and it was detected
immunohistochemically with polyclonal TrkA antibodies (sc-118,
Santa Cruz Biotechnology, Santa Cruz, CA, USA), as described
previously (Yamashiro et al., 2000a). Five rats were evaluated in
each group. To identify root-resorbing cells—i.e., odontoclasts and
osteoclasts—we stained the sections for tartrate-resistant acid
phosphatase (TRAP) activity, as described previously (Yamashiro
et al., 2000b).
Histometric Measurements and Bone Histomorphometry
We determined the width of the periodontal space on
hematoxylin-and-eosin-stained sections by measuring the distance
between the alveolar bone wall and cementum at the coronal
region of periodontal ligament tissue where acellular cementum is
distributed. Measurements were made every 30 ␮m along the
cellular cementum. To evaluate the states of alveolar bone
remodeling, we made the measurements and calculations for bone
histomorphometry according to the standard nomenclature
described by Parfitt et al. (1987). The histomorphometric
parameters were measured at the remodeling alveolar bone
surface that directly faces the periodontal ligament. In addition,
we also evaluated root resorption activity. Osteoblasts were
identified as cuboidal cells lining the bone surface. Osteoclasts
and odontoclasts were identified as TRAP-positive (red-staining)
cells situated at the bone or dentin surface, respectively, with
more than 3 nuclei. Active osteoclast and osteoblast surfaces were
defined as the bone surface adjacent to osteoclasts and osteoblasts,
respectively. The active odontoclast surface was also defined as
the root surface adjacent to odontoclasts. The numbers of
osteoclast (N.Oc) and osteoblast surfaces (Ob.S) were divided by
the remodeling bone surface (BS). The number of odontoclasts
(N. Od) was divided by the root surface (RS). Histometric
measurements were made with a semi-automatic image-analyzing
system consisting of a microscope (BX-60, Olympus, Tokyo,
Japan) and a CCD camera system (DP-70, Olympus, Japan). Five
rats were used for histometric measurements in each group, and 3
7-␮m sections at intervals of about 100 ␮m were examined in
each rat. The total number of TRAP-positive cells was counted in
identical regions (Fig. 3B), and the values were divided by the
total length of the root surface. The regions with degenerative
histological changes, i.e., ankylosis or hyalinization, were not
included in the area for this measurement. Significance was
determined by two-way analysis of variance (ANOVA) and
Scheffé's F test for post hoc comparison.
RESULTS
Nerve transection resulted in infrapositioning of the 2nd molars
relative to the adjacent teeth, a typical sign of dento-alveolar
ankylosis (Figs. 1A, 1B). Seven of 10, 8 of 10, and 9 of 10 rats
showed ankylosis 6 wks, 8 wks, and 10 wks after denervation,
respectively.
Microscopic observation confirmed the presence of
degenerative histological changes in denervated rats, localized
only in the furcation regions but not in the root apex regions
(Figs. 1C, 1D, 1E, 1F). Ten wks after denervation, resorption of
J Dent Res 83(8) 2004 Denervation and Dento-Alveolar Ankylosis 627

the degenerative tissues by TRAP-

positive cells was more evident than at
6 or 8 wks. We measured the width of
the periodontal space at the furcation
regions (Fig. 1G). The denervation
resulted in significant decreases in its
width at all stages observed (Fig. 1H).
Ten wks post-denervation, the rats
showed a significantly wider
periodontal ligament than at 8 wks,
while three-week-denervated rats did
not show any signs of dento-alveolar
ankylosis or histological degenerative
changes.
Epithelial cells showed a dense
distribution near the furcation (Figs.
2A, 2B). Many TrkA-immunopositive
epithelial rests of Malassez were
arranged in strands or as networks of
strands, as shown previously
(Yamashiro et al., 2000a) (Fig. 2B).
The denervation resulted in a marked
decrease in the distribution and the
sizes of clusters of TrkA-positive
epithelium in all stages (Figs. 2D-2S).
This change was evident from 1 wk
after denervation. However, the
distribution of the epithelium showed
slight recovery 10 wks after the
transection (Figs. 2G, 2K, 2O, 2S).
Malassez epithelium is localized at
the coronal periodontal space (Fig. 3A), Figure 2. The epithelial rests of Malassez showed immunoreactivity to TrkA. (A,B) Sagittal views of
and we analyzed bone modeling and the periodontal ligament and the epithelial rests of Malassez. Malassez epithelium was present at the
coronal regions of the periodontal ligament (A), and it was localized adjacent to the root surface in
root resorption activity. Denervation the PDL. (C) Diagram of sagittal sections. Serial horizontal sections of 50 ␮m were obtained near the
resulted in a significant increase in the furcation of the molar. (D,H,L,P) Coronal views of the serial sections of 50 ␮m in sham-operated
number of TRAP-positive odontoclasts rats. Samples were obtained 6 wks (E,I,M,O), 8 wks (F,J,N,R), and 10 wks (G,K,O,S) after
on the coronal sides of the root surface denervation. The inferior alveolar nerve denervation resulted in marked decreases in the size and the
distribution of TrkA-positive cell clusters. Arrowheads indicate the Malassez epithelium. Bar = 500
(Fig. 3C). On the remodeling bone ␮m for A and S. AB, alveolar bone; PDL, periodontal ligament; D, dentin.
surface in direct contact with
periodontal ligament tissues,
denervation increased the osteoblast
surface (Ob. S/BS) at 6 wks after
denervation (Fig. 3D). Significant differences were not observed process, therefore, there could be two possible etiologies of
at 8 or 10 wks. In contrast, denervation caused significant ankylosis, i.e., with or without the involvement of the Malassez
increases in the number of TRAP-positive osteoclasts (N. epithelium. Previous findings support the involvement of the
Oc./BS) at 6, 8, and 10 wks after denervation (Fig. 3F). Malassez epithelium—i.e., transplanted enamel epithelium
In sham-operated rats, coronal regions of the root surface maintained the periodontal space between the surrounding
(Fig. 3A) were covered by acellular but not by cellular alveolar bone and the cementum (Lindskog et al., 1988).
cementum. In contrast, denervation led to the induction of However, a tooth germ can develop to form the normal
cellular cementum formation in all denervated rats 6, 8, and 10 periodontal ligament in a kidney capsule, indicating that
wks after inferior alveolar nerve transection (Fig. 3D, Table). periodontal mesenchymal cells can differentiate without the

DISCUSSION Table. Frequency of Induction of Cellular Cementum on the Coronal

In the present study, denervation of the inferior alveolar nerve Root Surfacea
resulted in 2 major events, i.e., a reduced distribution of the
Malassez epithelium, as shown previously (Yamashiro et al., 6w 8w 10w
2000a), and dento-alveolar ankylosis. Denervation led to a
decreased distribution after 1 wk (Yamashiro et al., 2000a), Sham 0 (5) 0 (5) 0 (5)
while dento-alveolar ankylosis was detected after 6 wks, DN 5 (5) 5 (5) 5 (5)
indicating that a reduction in the Malassez epithelium
distribution preceded the development of ankylosis. In this a Data are shown as # of inductions (N).

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628 Fujiyama et al. J Dent Res 83(8) 2004

remodeling alveolar bone surface facing the

periodontal ligament with development of ankylosis.
However, bone formation was not activated by
denervation at the remodeling alveolar bone surface
when it was evaluated before the formation of
ankylosis (Yamashiro et al., 2000b). These findings
suggested that denervation itself did not affect bone
formation and that the histomorphometric index was
elevated during the process of ankylosis formation.
Currently, we do not completely understand how the
periodontal space is maintained. As mentioned
earlier, transplanted dental epithelium prevented the
surrounding alveolar bone from migrating to the
periodontal space, and the space between the
epithelium and the bone appeared to maintain an
almost constant width (Lindskog et al., 1988). It is
known that some periodontal ligament cells express
Osf2/Cbfa1, a key regulator of osteogenic
differentiation. This expression indicates that
periodontal ligament cells have already acquired an
osteogenic property; however, some mechanism
might prevent the periodontal cells from being
mineralized in the periodontal space (Saito et al.,
2002). One possible explanation for the maintenance
of periodontal space is that some molecules are
released from cell compartments localizing at the
root surface, i.e., Malassez epithelium and
cementoblasts, which inhibit osteogenesis in the
Figure 3. Red line in (A) shows the region covered by acellular cementum (ac) in periodontal space. Hence, it is possible that, in the
control mice. TRAP-positive cells were present on both the root and the alveolar bone present study, the disappearance of Malassez
surface in sham (B) and denervated rats (C) at 6 wks. (D) TRAP-positive odontoclasts
epithelium resulted in the disruption of the putative
were measured on the root surface as shown in red in (A). (E,F) Bone
histomorphometric indices of the osteoblast surface (E) and osteoclast number (F) inhibitory role against ossification in the periodontal
were also measured on the modeling alveolar bone surface. (G) Denervation induced space, and that adjacent bone might consequently
cellular cementum (cc) formation among the acellular cementum regions at 6 wks, as grow into the periodontal ligament space, causing
shown in red in (A). All data are mean ± SD (n = 5/group). *Significantly different dento-alveolar ankylosis.
from the values in sham rats (P < 0.05). a, significantly different from the values in
6w- and 8w-DN rats (P < 0.05). cc, cellular cementum; DN, denervated rats; D, The present findings also showed that osteoclasts
dentin; AB, alveolar bone; PDL, periodontal ligament. Bar = 100 ␮m for C and G. and the number of odontoclasts also significantly
increased with the disappearance of Malassez
epithelium. These findings suggest that Malassez
epithelium plays some inhibitory role in osteoclast or
odontoclast appearance. However, degenerative tissues
involvement of sensory innervation (Luukko et al., 1997). were frequently observed between the root and bone surfaces at 6
Therefore, it is unlikely that denervation directly caused wks. It is also possible that increased odontoclast and osteoclast
degenerative histological changes in periodontal mesenchymal numbers might indicate some mechanism in the periodontal
tissues that could consequently cause ankylosis. The present ligament which would remove the degenerative tissues and
histological observation showed that dento-alveolar ankylosis consequently serve to prevent ankylosis. Thereafter, with increases
was present only on the coronal root surface, where the in the periodontal ligament at 10 wks, the osteoclast number was
Malassez epithelium is located, and that there were no further increased. Hence, it is likely that activated bone resorption
degenerative changes detected in the apical periodontal ligament might contribute to recovery of the periodontal space.
region, which is densely innervated by the sensory nerve. In The coronal root surface is normally covered by acellular
addition, the reduced periodontal space width increased again cementum (Diekwisch, 2001); however, denervation resulted in
between 8 and 10 wks after denervation, when the epithelium the induction of cellular cementum at that site. Probably, the
recovered, presumably by regeneration. Our findings, together denervation stimulated root resorption, as evidenced by the
with previous data, suggest that Malassez epithelium could be increased number of TRAP-positive odontoclasts. The resorbed
involved, at least in part, in maintaining the periodontal space cementum lacunae were then repaired by the formation of
width. In other words, it might prevent alveolar bone cellular, but not acellular, cementum. It has been proposed that
compartments from migrating into the cementum surface. the epithelial rests of Malassez might be directly involved in
Bone histomorphometry provided some insight into the cementum formation through epithelial-mesenchymal
mechanism involved in the development of dento-alveolar interaction (Ten Cate, 1996). An anatomical study showed this
ankylosis in denervated rats. The bone histomorphometric epithelium was localized close to the acellular cementum
indices suggested that bone formation was activated along the surface that was present at the coronal half of the root surface

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J Dent Res 83(8) 2004 Denervation and Dento-Alveolar Ankylosis
(Formicola et al., 1971), but not close to the cellular cementum
localized at the apical surface in the early stage of root
formation (Kagayama et al., 1998). The present findings are in
accord with these findings and support the idea that Malassez
epithelium may play a role in the induction of acellular
cementum, presumably via epithelial-mesenchymal interactions.
In addition to the putative function of the Malassez epithelium
in the maintenance of the periodontal space, results from a
previous study suggested that this epithelium has auto- or
paracrine stimulatory functions in the process of reparative
cementum formation (Sismanidou et al., 1996). In this study,
immunoreactivity to epidermal growth factor (EGF) receptors was
up-regulated in epithelium close to a healing resorption. The
present study showed that active cementum formation was evident
at 10 wks. Since the Malassez epithelium started to regenerate at
this stage, our finding might also support this putative function of
the Malassez epithelium in cementum formation.
Although the present study showed the significance of the
Malassez epithelium in maintenance of the periodontal space,
the Malassez epithelium is predominantly localized on the
coronal side of the periodontal ligament, but much less on the
apical side. Therefore, other mechanisms must contribute to
maintaining the width of the periodontal space in the apical
regions. It is possible that cementum might also contain
putative molecules that regulate the periodontal space width
along with the epithelial rests of Malassez.
In summary, we found that denervation of the inferior
alveolar nerve led to dento-alveolar ankylosis on the coronal
root surfaces. Our histological observations, along with
previous findings, showed that Malassez epithelium could
regulate, at least in part, the maintenance of the periodontal
ligament. In addition, denervation resulted in activation of root
resorption at the coronal periodontal ligament, and the
consequently resorbed lacunae were repaired by cellular
cementum formation, suggesting that the Malassez epithelium
might be directly or indirectly involved in root resorption and
differentiation of acellular cementum.
ACKNOWLEDGMENT
This study was supported by Grants-In-Aid for Scientific
Research from Japan Society for the Promotion of Science
(14207092, 14571948, 15390635, and15659491).
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