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Inheritanceofsusceptibilitytorootresorption
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ORIGINAL ARTICLE
Inheritance of susceptibility to root resorption
associated with orthodontic force in mice
Shaza K. Abass,a James K. Hartsfield, Jr.,b Riyad A. Al-Qawasmi,c Eric T. Everett,d Tatiana M. Foroud,e
and W. Eugene Robertsf
Khartoum, Sudan, Lexington, Ky, Indianapolis, Ind, Canton, Mich, and Chapel Hill, NC
Introduction: External apical root resorption (EARR) is an unwanted sequelae of orthodontic treatment.
Genetic factors account for approximately 64% of the EARR variation in humans. Inbred mice offer a model
to control the environmental factors and genetic heterogeneity that complicate human genetic studies.
Genetically distinct inbred mice and their offspring (F1s) were analyzed to examine the mode of inheritance
and the influence of parental sex on the susceptibility to root resorption associated with orthodontic force
(RRAOF). Methods: RRAOF was determined histologically for male and female mice of the A/J, DBA/2J, and
BALB/cJ strains, and the A/J ⫻ DBA/2J and A/J ⫻ BALB/cJ crosses (10 males and 10 females/reciprocal
cross). RRAOF was induced by tipping the maxillary first molar mesially for 9 days. Results: Sex differences
were observed only among the mice of the BALB/cJ strain. Two patterns of inheritance were observed; F1s
from the A/J ⫻ BALB/cJ cross were resistant, suggesting that the A/J have dominant resistance alleles. On
the other hand, F1s from the A/J ⫻ DBA/2J cross showed RRAOF intermediate between their parental mice,
suggesting a polygenic trait. Conclusions: These results provide evidence of a traceable and polygenetic
component affecting RRAOF in mice. (Am J Orthod Dentofacial Orthop 2008;134:742-50)
E
xternal apical root resorption (EARR) is a clinical
complication of orthodontic tooth movement that
is detected radiographically.1,2 There is significant variation in EARR susceptibility among patients.1
Although familial clustering of EARR was reported in
1975,3 no clear pattern of inheritance has been identified. Sibling-pair models have shown a heritability
estimate of 0.8 for the maxillary incisors.1,4 This
genetic variation accounts for approximately 64% of
the total phenotypic (clinical) variation. Ethnic dichotomy has also been reported, with Asian patients having
less EARR than white or Hispanic patients; this might
represent the effect of some combination of genetic and
a
Assistant professor of dental science, University of Khartoum, Sudan.
Professor and E. Preston Hicks Endowed Chair in Orthodontics and Oral
Health Research, Department of Oral Science, College of Dentistry, University
of Kentucky, Lexington, Ky.
c
Private practice, Canton, Mich.
d
Associate professor, Department of Pediatric Dentistry; Carolina Center for
Genome Sciences, University of North Carolina, Chapel Hill.
e
P. Michael Conneally professor and director, Division of Hereditary Diseases
and Family Studies, Department of Medical and Molecular Genetics, School of
Medicine, Indiana University, Indianapolis.
f
Professor emeritus, Department of Orthodontics and Oral Facial Genetics,
School of Dentistry, Indiana University, Indianapolis.
Supported by Public Health Service grants T32 AR07581-60 (D. Burr) and F32
DE16543-01A1 (S.K.A.).
Reprint requests to: James K. Hartsfield, Jr., Orthodontic Graduate Program,
University of Kentucky College of Dentistry, 800 Rose Street, Room D416,
Lexington, KY 40536-0297; e-mail, [email protected].
Submitted, June 2006; revised and accepted, April 2007.
0889-5406/$34.00
Copyright © 2008 by the American Association of Orthodontists.
doi:10.1016/j.ajodo.2007.04.035
b
742
environmental factors.5 A more recent retrospective
twin study on EARR showed that the concordance scores
for monozygotic twins were approximately twice those of
dizygotic twins, indicating a strong genetic influence on
EARR, whereas the concordance for identical twins was
less than 100%, indicating environmental effects.6 Both
linkage and association analyses indicate that variations
in the IL-1B gene influence EARR, accounting for 15%
of the total variation in EARR in 1 clinical sample.7
The influence of the lack of IL-1␤ was also seen in a
mouse IL-1b knockout model, resulting in increased
root resorption (RR) lacunae.8 Linkage analysis indicated that the variable number of tandem repeats of the
DNA marker D18S64 is linked to a gene on chromosome 18 that is also involved with EARR.9
RR, another phenomenon associated with orthodontic and biting forces, occurs on all areas of the root
under compression. RR usually shows as microscopic
areas of resorption on root surfaces histologically.
Seventy-five percent of RR sites show complete repair
with secondary cementum.10 Orthodontic force applied
to teeth for a short time can produce histologic RR with
no radiographically visible EARR.11 Any factor that
increases RR, including increases in duration and magnitude of orthodontic force, can result in the exposure
of root dentin underlying the damaged cementum. This
exposed dentin increases the likelihood of odontoclast
attack that exceeds its reparative capacity and results in
EARR (Fig 1).12-14
American Journal of Orthodontics and Dentofacial Orthopedics
Volume 134, Number 6
Fig 1. Application of an orthodontic force results in an
increase in histologic RR, which is followed by repair
with secondary cementum in most cases. When RR
exceeds the reparative capacity of cementum, we see
EARR radiographically.
Inbred mouse strains offer many advantages for the
analysis of the genetic contribution to disease susceptibility. Members of each inbred strain are genetically
identical and homozygous at all loci. Inbred strains and
strict control of environmental factors allow for the
exploration of how allelic variation in different strains
modifies the susceptibility to complex diseases. Since
each inbred mouse strain is genetically different from
other inbred strains, selective crossing of susceptible
and resistant strains is a powerful tool for identifying
genes that play major roles in complex diseases. A
study of histologic RR in 8 inbred strains of mice after
application of orthodontic force found that A/J male
mice were among the most resistant to RR associated
with orthodontic force (RRAOF). The DBA/2J and
BALB/cJ inbred male mice were among the most
susceptible.15 The same mouse model was used in this
study to examine sex (male vs female) differences
among the A/J, DBA/2J, and BALB/cJ mouse strains.
The mode of inheritance that conveys susceptibility to
RRAOF was analyzed in these mouse strains and their
offspring (F1s).
MATERIAL AND METHODS
All experimental procedures were approved by the
Indiana University School of Dentistry Institutional
Animal Care and Use Committee. Female A/J (n ⫽ 20),
DBA/2J (n ⫽ 20), and BALB/cJ (n ⫽ 20) inbred mice
Abass et al 743
were obtained from the Jackson Laboratory (Bar Harbor, Maine). CAF1 (F1 of BALB/cJ females ⫻ A/J
male) males (n ⫽ 20) and females (n ⫽ 20) were
obtained from the same source. The animals were
purchased at 8 weeks of age and acclimated for 1 week.
The other 3 crosses were generated at the Indiana
University School of Dentistry Bioresearch Facility
because they are unavailable commercially. These were
ACF1 (A/J female ⫻ BALB/cJ male) males (n ⫽ 20)
and females (n ⫽ 20), AD2F1/J (A/J females ⫻
DBA/2J males) males (n ⫽ 20) and females (n ⫽ 20),
and D2AF1/J (DBA/2J females ⫻ A/J males). The total
number of animals analyzed was 180.
All mice were housed in the Indiana University
School of Dentistry Bioresearch Facility. Both the
control and the treated animals were fed finely milled
mouse chow with tap water ad libitum. This special diet
was used to minimize discomfort and appliance distortion in the mice that received orthodontic treatment. All
mice were weighed daily.
At 9 weeks of age, 10 male and 10 female mice
representing each strain were randomly selected to be
treated with an orthodontic appliance to tip the maxillary first molar mesially. Weights were recorded, and
anesthesia was obtained by intraperitoneal injection of
0.35 mL per 25 g of body weight of anesthetic cocktail
(ketamine, xylazine, saline solution, 10:2:1). After
anesthesia, a 0.006 ⫻ 0.022-in HI-T coil spring (3M
Unitek, Monrovia, Calif) was used to apply 25 g of
force between the first maxillary molar and the incisor
as described previously.15 Briefly, 1 end of the coil
spring was attached to the left maxillary first molar with
a 0.007-in ligature wire (Rocky Mountain Orthodontics, Denver, Colo). The coil spring was then activated
by pulling a black braided silk suture (Ethicon, Somerville, NJ) attached to the anterior end of the spring.
The amount of force was measured with a Dontrix
orthodontic gauge (E.T.M., Monrovia, Calif). After
activation, the ligature was bonded to the maxillary
incisors by a light-cured composite resin (Orthodontic
Bonding Adhesive, Ormco/ Syrbron, Glendora, Calif).
Ten mice per experimental group were used as controls.
After 9 days of treatment or remaining as controls, the
animals were killed by carbon dioxide inhalation.
Each maxilla was harvested and fixed in 10% cold
neutral buffered formalin for 24 hours and decalcified
in 0.25 mol/L ethylenediaminetetraacetic acid (EDTA)
and 2% formalin (pH 7.2) for 4 weeks at 4°C. The
EDTA solution was changed every day for the first 3
days and then every week. To ensure complete decalcification, selected samples were radiographed. Thereafter, the samples were dehydrated and embedded in
paraffin. The embedded specimens were cut into para-
744 Abass et al
sagittal sections 5 ␮m thick as parallel as possible to the
long axis of the mesial root of the first molar and
mounted on glass slides.
Tissue sections were arranged on glass slides so that
each slide had 4 consecutive sections. For each mouse,
every fourth glass slide was stained with hematoxylin
and eosin (H&E). To identify osteoclasts and odontoclasts, 3 randomly selected slides were stained for
tartrate resistant acid phosphatase (TRAP), according
to the manufacturer’s methods (leukocyte acid phosphatase kit, Sigma Diagnostics, St Louis, Mo). Briefly,
deparaffinized slides were incubated in Coplin jars
containing diazotized fast garnet, napathol AS-BI phosphate acetate, and tartrate solution for 1 hour in a 37°C
water bath. Sections were rinsed in distilled water and
counterstained with hematoxylin.
Quantification of RR on H&E stained sections was
performed as previously described by Lu et al.16 The
mesial aspect of the mesial root of the maxillary first
molar was analyzed by using light microscopy at 100
times magnification. A 10 ⫻ 10 grid was used to
determine the RR percentage by counting grids with
and without resorption lacunae. The grid was oriented
parallel to the long axis of the mesial root of the
maxillary first molar, covering the area from the cementoenamel junction to the root apex. The RR percentage was calculated by dividing the number of grids
with resorption lacunae by the total number of grids
along the root surface. The total percentage of resorption for each mouse was determined by adding the RR
percentages for all sections and then dividing that by
the total number of sections. Mean root resorption
(MRR) for each strain and sex was then calculated. In
the treatment group, the RRAOF for each strain and sex
was calculated by subtracting the MRR of the control
group from that of the treatment group. The calculated
RRAOF factored out baseline RR, which is not associated with orthodontic force.
TRAP-positive stained cells were examined on the
periodontal ligament interface of the mesial side of the
mesial root of the maxillary first molar. By using 400
times magnification, the number of TRAP-positive
cells in 50 ␮m of the root surface was counted from the
cementoenamel junction to the root apex.
To evaluate the reliability of RR and TRAP-positive cell measurements, 50 sections were selected
randomly and remeasured. The second measurements
were made blindly 2 months after the first measurements under similar conditions by the same examiner
(S.K.A.). A paired t test was used for data analysis. The
significance level was set at ␣ ⫽ 0.05. No significant
differences were found between the 2 sets of measurements.
American Journal of Orthodontics and Dentofacial Orthopedics
December 2008
Statistical analysis
A 2-sample t test was used to (1) compare RRAOF
between males and females, (2) determine whether the
RRAOF values for the F1s were the same if the
susceptible parent mouse was female or male, and
(3) examine whether RRAOF measurements in the F1s
were significantly different from those of the parent
mice. The significance level was set at ␣ ⫽ 0.05. All
data are expressed as means ⫾ SEM.
RESULTS
The mice tolerated the appliance well. An initial
weight loss after surgery was observed in all animals,
but they started to gain weight 3 days after appliance
placement. The BALB/cJ strain was the slowest to
regain weight, but overall weight loss did not exceed
15% of original weight.
Male and female A/J, BALB/cJ, and DBA/2J parent
mice showed a significant increase in MRR with
treatment (P ⬍ 0.0001). Comparing RRAOF for males
and females of the same strain, the A/J males tended to
have slightly higher values of RRAOF than the females; DBA/2J males tended to have slightly lower
RRAOF than the females. In both of these strains, the
differences were not statistically significant (P ⫽ 0.39
and P ⫽ 0.1, respectively). The RRAOF values for the
BALB/cJ males were 9 times more than those of the
BALB/J females (P ⬍0.0001) (Fig 2).
To determine whether the parents’ sex plays a
major role in the inheritance of susceptibility to
RRAOF of F1s, differences in RRAOF were examined
in the various crosses. No significant difference was
found in the values of RRAOF whether the resistant or
susceptible parent was male or female; these data
exclude a parent-of-origin effect (Fig 3).
RRAOF in the F1 animals from the crossings A/J
females ⫻ DBA/2J males, DBA/2J females ⫻ A/J
males, A/J females ⫻ BALB/cJ males, and BALB/cJ
females ⫻ A/J males was examined in comparison with
that of their parental strains. The RRAOF value for the
female F1s of the A/J female ⫻ DBA/2J male cross
(AD2F1/J) was significantly different from the parental
A/J females (P ⫽ 0.00005) and DBA/2J males (P ⫽
0.012) (Fig 4). Male F1s from that cross also had
RRAOF values that were significantly higher that thoe
of the female A/J parent mice (P ⫽ 0.001), but not
statistically different (P ⫽ 0.23) from that of the male
DBA/2J parents.
In the reciprocal cross, DBA/2J females ⫻ A/J
males (D2AF1/J), the female F1s RRAOF values were
significantly different from the both the parental
DBA/2J females and the A/J males (P ⫽ 0.001 and P ⬍
American Journal of Orthodontics and Dentofacial Orthopedics
Volume 134, Number 6
Abass et al 745
Fig 2. RRAOF in A/J, DBA/2J, and BALB/cJ mice. Each point represents the mean RRAOF ⫾ SEM. A
statistically significant difference was observed only among the BALB/cJ males and females (n ⫽ 10).
Fig 3. Comparing the RRAOF in the F1 mice resulting from (1) crossing A/J females to DBA/2J
males (AD2F1/J); (2) reciprocal crossing of DBA/2J females to A/J males (D2AF1/J); (3) crossing A/J
females to BALB/cJ males (ACF1/J); (4) reciprocal crossing of BALB/cJ females to A/J males
(CAF1/J). The test yielded insignificant P values, indicating no parent-of-origin effect. Each point
represents the mean RRAOF ⫾ SEM (n ⫽ 10).
0.001, respectively). The male F1s from that cross also
had RRAOF values that differed significantly from both
their female DBA/2J and male A/J parents (P ⫽ 0.05
and P ⫽ 0.00005, respectively) (Fig 5).
For the A/J females ⫻ BALB/cJ males (ACF1/J)
cross, both female and male F1s had RAOFF values
similar to those of the resistant A/J females (P ⫽ 0.45
and P ⫽ 0.09, respectively) and statistically different
from those of the BALB/cJ susceptible males (P ⫽
0.001 and P ⫽ 0.0002, respectively) (Fig 6). The
746 Abass et al
American Journal of Orthodontics and Dentofacial Orthopedics
December 2008
Fig 4. RRAOF in mice from the A/J females ⫻ DBA/2J males cross. The male F1s had RRAOF
similar to the parent male mice but significantly different from the female parent. Female F1s had
RRAOF values that were statistically different from their male and female parents. Each point
represents the mean RRAOF ⫾ SEM (n ⫽ 10).
Fig 5. RRAOF in mice from the DBA/2J females ⫻ A/J males cross. The male and female F1s had
RRAOF values statistically different from their male and female parents. Each point represents the
mean RRAOF ⫾ SEM (n ⫽ 10).
RRAOF values for the male and female F1s from the
cross between BALB/cJ females ⫻ A/J males (CAF1/J)
were also similar to the A/J male resistant mice (P ⫽
0.49 and P ⫽ 0.24), and statistically different from the
BALB/cJ mice (P ⫽ 0.04 and P ⫽ 0.08, respectively)
(Fig 7).
TRAP-positive cells were not found in most untreated animals. When treatment was introduced, the
number of TRAP-positive cells increased significantly
in all tested strains. The values for the number of
TRAP-positive cells were consistent with the RR percentages for all strains. However, there was no consis-
American Journal of Orthodontics and Dentofacial Orthopedics
Volume 134, Number 6
Abass et al 747
Fig 6. RRAOF in mice from the A/J females ⫻ BALB/cJ males cross. The male and female F1s had
RRAOF values similar to their resistant A/J male parents. Each point represents mean RRAOF ⫾
SEM (n ⫽ 10).
Fig 7. RRAOF in mice from the BALB/cJ females ⫻ A/J males cross. The male and female F1s had
RRAOF values similar to their resistant BALB/cJ female parents. Each point represents mean
RRAOF ⫾ SEM (n ⫽ 10).
tent correlation between RRAOF and TRAP for any
specific strain.
DISCUSSION
There is considerable individual variability in the
susceptibility to EARR. Environmental factors related
to treatment, including mechanical loading of teeth,
force magnitude and direction, and duration of treatment play roles in the manifestation of EARR; however, they did not fully explain the differences in
susceptibility. Genetic factors are believed to play a
major role in determining individual susceptibility to
RRAOF. Even when treatment and practitioner factors
are constant, there is great variation in a patient’s
748 Abass et al
susceptibility to EARR. Heritability estimates in humans showed that genetic risk factors can explain
approximately 64% of the variability of EARR associated with orthodontic treatment. This indicates a complex (quantitative) trait in which both genetic and
environmental factors play roles.4 Linkage and association studies identified 2 genes that might explain some
of the genetic component of this trait, although the
genes accounting for most of the nonenvironmental
variation remain unknown.7,9 Unlike so-called simple
Mendelian traits that are essentially mediated by a
single gene, complex traits are usually derived from
interactions of many genes and environmental factors.
Multiple genetic factors play a role in a complex trait,
with no single gene by itself causing the disease (trait).
This makes the identification of genes that modulate a
complex trait such as RRAOF a challenging task.
Quantitative trait loci (QTL) are chromosomal regions that contain genes that modulate a quantitative
trait such as RRAOF. The identification of such chromosomal regions that contribute to the susceptibility to
RRAOF is an essential step toward understanding the
disease mechanism. The genetic heterogeneity of a
population and uncontrolled environmental factors render this kind of analysis difficult to perform in humans.
The use of inbred strains of mice is a practical means
for controlling the factors that complicate human studies. The genomic conservation of mice gene order with
humans (synteny) and the high degrees of homology
(80%) with human gene sequences make inbred mice a
perfect model for studying QTL, which can then be
applied to humans.17-19 The availability of a dense and
detailed genetic map makes gene mapping in mice a
practical and efficient way for determining candidate
chromosomal sites and testing them in human association studies.
The application of 25 g of force to move teeth is a
relatively high force level.20 This force is high enough
to cause tooth movement but low enough to permit the
differentiation and migration of resorbing cells.21 Some
other models used mandibular molars, since it is
thought that better retention can be achieved.22 In our
model, we did not encounter any problem with retention, perhaps because, instead of bonding the spring
attachment to the occlusal surface of the mandibular
molar, the spring was ligated to the crown of the
maxillary molar. Also in previous models, it was
necessary to remove the opposing tooth because of the
bonding of the occlusal surface. This mouse model was
a modification of another model developed to study the
transduction of mechanical signals into a biologic
response.8,15,23
American Journal of Orthodontics and Dentofacial Orthopedics
December 2008
We used histologic sections to quantitate RRAOF.
To minimize errors to different tissue localization,
sections of the maxilla were cut and oriented in the
same manner for all animals. Furthermore, every fourth
glass slide was stained with H&E and examined for
each mouse. The use of a grid was described as a
reliable method for analysis of RR in several studies.8,15,16
Although most human studies found no sex differences in EARR,24-30 a few reported greater incidence
among females31-34 or males.2,35 Most of these studies
did not control for severity of the malocclusion, treatment variables, or patient factors. In this study, the only
significant difference was in the susceptibility to
RRAOF of the BALB/cJ mice, with the males more
susceptible to RRAOF than the females. This makes the
BALB/cJ mice an excellent model to explore sexrelated differences that govern the susceptibility to
RRAOF in mice in a more controlled manner than in
humans. Differential actions of sex steroids, genetic
imprinting36 (the silencing of maternal or paternal
genes), and the interplay of the sex chromosomes with
other autosomal genes (epistasis)37 are possibilities that
can explain such differences. The fact that sex differences were found in 1 strain implies that these differences are strain dependent. This leads us to believe that
epistasis is an important element of this trait. This
implies that it is not only the sex that determines the
susceptibility to RRAOF. The underlying genetic
makeup of a subject could put either sex at higher
susceptibility to RRAOF. Thus, some patients might be
more susceptible to EARR depending on their particular genetic background. Sex-specific QTL have been
described in several phenotypes in mice. Examples
include femoral cross-sectional area,38 stress-induced
analgesia,39 and alcohol preference.40
Reciprocal crosses showed no parent-of-origin (imprinting or maternal) effect on the trait expression.
Reciprocal F1 hybrid mice are expected to differ in the
Y chromosome (carried by males), the maternally
derived mitochondrial genome, and potential imprinting. A parent-of-origin effect was not found in any
crosses; this means that the parent’s sex was not a
significant factor in the inheritance of the susceptibility
to RRAOF.
For the A/J (resistant) strain and DBA/2J (susceptible) cross, the F1s’ susceptibility to RRAOF was
somewhere between that of both the A/J and DBA/2J
strains, except for the AD2F1 males, which had
RRAOF susceptibility closer to that of the male parental DBA/2J strain. These results suggest that a polygenic trait involving many genes will better explain the
genetic influence in this cross. The cross between the
Abass et al 749
American Journal of Orthodontics and Dentofacial Orthopedics
Volume 134, Number 6
A/J and BALB/cJ mice was more complicated because
we had to consider the sex of the parent separately,
since the male BALB/cJ mice were susceptible to
RRAOF compared with the females. In a cross of A/J
females (resistant strain) with BALB/cJ males (susceptible), the F1 hybrids were significantly different from
both the BALB/cJ males but was more closely related
to the A/J female values. Data from this cross indicate
that a single gene might be influential, and that the A/J
mice carry a dominant resistant gene. However such a
dominant effect was not seen when the A/J mice were
crossed with the other susceptible DBA/2J mice. A
backcross of the F1s from the A/J ⫻ BALB/cJ and
BALB/cJ will be necessary to determine whether there
is a pattern of dominance. The DBA/2J ⫻ A/J cross
would be an excellent model for another intercross to
produce F2 animals for further QTL analysis. QTL
analysis has been successfully exploited in identifying
the genetic loci of importance in animal models expressing hypertension,41 diabetes, atherosclerosis, and
airway responsiveness.42
When the BALB/cJ females (resistant) were
crossed with the A/J males (resistant), all F1s had
RRAOF values similar to the A/J mice. This cross did
not provide information about the mode of inheritance
of the trait, since both parental strains are resistant to
RRAOF; however, it showed that F1s have RRAOF
values similar to their parents, confirming the heritability of the trait.
Accordingly, the genetic influences on the susceptibility to RRAOF appear to be polygenic with a
possible major gene influence. F1 progeny from a
resistant strain (A/J) and 2 susceptible strains of mice
(DBA/2J and BALB/cJ) showed different susceptibilities to RRAOF depending on the cross.
CONCLUSIONS
We demonstrated that the susceptibility to RRAOF
is a heritable trait in mice. Thus, inbred mice are
valuable for dissection of the trait and further understanding of the disease mechanism. Further analysis of
F2 animals through QTL analysis would be helpful for
identifying areas of DNA that include genes that
influence the susceptibility to RRAOF. Ultimately,
defining critical loci in mice and applying this knowledge to humans will allow for the testing of candidate
genes that can be linked or associated with RRAOF.
This knowledge could have a practical application in
screening prospective orthodontic patients for susceptibility to RRAOF before treatment.
We thank Patsy A. Dunn-Jena for assistance with
the animal surgery and technical advice regarding
histology, and Marjorie Weaver for statistical consultation during the study.
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