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Ontogeny of Skeletal Maturation in the Juvenile Rat.

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THE ANATOMICAL RECORD 291:283–292 (2008)
Ontogeny of Skeletal Maturation
in the Juvenile Rat
JASON A. HORTON,* JASON T. BARITEAU, RICHARD M. LOOMIS,
JUDITH A. STRAUSS, AND TIMOTHY A. DAMRON
SUNY Upstate Medical University, Department of Orthopedic Surgery,
3120 Institute for Human Performance, Musculoskeletal Sciences Research Center,
Syracuse, New York
ABSTRACT
Systemic regulation of the cellular processes that produce endochondral elongation and endochondral mineralization during postnatal skeletal
maturation are not completely understood. In particular, a mechanism coupling the decline of cellular activity in the bone microenvironment to the
onset of sexual maturity remains elusive. The purpose of this study was to
empirically integrate the dynamic progression of bone mineral accrual and
endochondral elongation as a function of animal age in growing male and
female Sprague-Dawley rats. We used serial dual-energy X-ray absorptiometry (DXA) and radiography to study the temporal progression of bone
growth and mineral accrual from weaning to adulthood. We observed that
skeletal maturation proceeds in a pattern adequately described by the
Gompertz function. During this period of growth, we found that serum
markers of osteoblastic bone formation declined with age, while osteoclastic bone resorption activity remained unchanged. We also report a slight
lag in the age at inflection in the rate of bone mineral accrual relative to
the rate of tibial elongation and that both endochondral processes eventually come to asymptotic equilibrium by approximately 20 weeks of age. In
addition, we studied tibial growth plate histomorphometry at select time
points through 1 year of age. We report that, despite the histologic persistence of physeal cartilage, very little proliferative or elongative activity was
measured in this tissue beyond 20 weeks of age. Taken together, these data
provide insight to the temporal coordination of postnatal endochondral
growth processes. Anat Rec, 291:283–292, 2008. Ó 2008 Wiley-Liss, Inc.
Key words: skeletal maturation; DXA; endochondral mineralization; endochondral elongation; osteocalcin; TRAP5b;
bone density
Conceptually, postnatal skeletal maturation in mammals may be considered an ex utero extension of a developmental process begun early in embryonic life (Tuan,
2004; Provot and Schipani, 2005). From the onset of
chondrogenesis in the developing limb bud, the processes
of endochondral elongation and endochondral ossification proceed along a nearly exponential trajectory
(Goldring et al., 2006). However, as the individual ages,
this growth rate subsequently declines toward asymptote as sexual maturation is achieved (Kilborn et al.,
2002). However, the mechanism coupling of these processes is not well understood (Engelbregt et al., 2004).
The rapid progression of postnatal development in the
Sprague-Dawley rat combined with recent developments
Ó 2008 WILEY-LISS, INC.
Grant sponsor: NIH/NCI-RO1; Grant number: CA83892;
Grant sponsor: David G. Murray Endowment.
*Correspondence to: Jason A. Horton, SUNY Upstate Medical
University, Department of Orthopedic Surgery, 3120 Institute
for Human Performance, Musculoskeletal Sciences Research
Center, 505 Irving Avenue, Syracuse, NY 13210. Fax: 315-4646638. E-mail: hortonj@upstate.edu
Received 7 February 2007; Accepted 18 November 2007
DOI 10.1002/ar.20650
Published online 29 January 2008 in Wiley InterScience (www.
interscience.wiley.com).
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HORTON ET AL.
in various radiologic, biochemical, and histomorphometric methodologies make this organism an attractive
model for the study of skeletal maturation. Radiographic
technologies such as dual-energy X-ray absorptiometry
(DXA) and quantitative computed tomography (QCT)
are widely used in clinical bone densitometry. Recently,
these imaging modalities have been developed for use
with small animal laboratory models, providing the basic
scientist with data that are clinically relevant and readily translated (Ammann et al., 1992; Horton et al.,
2003). Similarly, histomorphometric, biochemical, and
serological methods have been developed to determine
the rate of osteoblastic bone synthesis, osteoclastic bone
resorption, and growth plate chondrocyte proliferation
occurring in the bone microenvironment. Although data
regarding skeletal growth and mineral content have
been available for almost a century (Donaldson, 1915),
few investigators have endeavored to study the process
of skeletal maturation by combining radiologic, histomorphometric, and serologic approaches as we have here
in a commonly used laboratory small animal. The purpose of this study was to integrate, as a function of animal age, the dynamic processes of bone mineral accrual
and endochondral elongation from weaning to growth
equilibrium. We hypothesized that these processes would
conform to the Gompertzian growth function and that
there would be a strong association between the rate of
bone elongation, mineralization, and the metabolic activity of the cells that are directly responsible for promotion of the aspects of skeletal maturation in rats.
MATERIALS AND METHODS
Animal Subjects and Husbandry
Weanling 28-day-old male (n 5 6) and female (n 5 6)
Sprague-Dawley rats (Taconic Farms, Germantown, NY)
were selected for serial examination of bone density and
longitudinal growth. Five additional groups of n 5 3
male rats each 42, 63, 112, 140, and 350 days old were
obtained to provide tissue for histomorphometry. In the
laboratory, this species has been reported to achieve sexual maturity at 45–55 days in males and 36–38 days in
females (Ojeda and Urbanski, 1994; Engelbregt et al.,
2004). All animals were housed three-per-cage under
ambient conditions of 228C and 50% humidity. All animals had ad libitum access to standard rat chow and tap
water. Daily photoperiods were 12-hr light/dark. Animals were allowed to acclimatize to the local environment for 1 week before study initiation. At the conclusion of the study, all animals were humanely euthanized
by carbon dioxide inhalation. All experimental procedures described in this study were performed according
to a protocol approved by our Institutional Animal Care
and Use Committee.
Radiography and DXA Bone Densitometry
Beginning at 28 days of age, and on a semiweekly
schedule thereafter, all animals in each of the two
groups of six rats each were anesthetized by an intramuscular injection of a tiletamine/zolazepam cocktail (30
mg/kg Telazol, Fort Dodge Animal Health, Fort Dodge,
IA). Upon sedation, animals were placed in a supine posture and immobilized in such a manner that the hip,
knee, and ankle joints were held at 90 degrees flexion
(Horton et al., 2003). The animals were then positioned
on the scanning bed of the PIXImus2 (GE-Lunar, Madison, WI) small animal research DXA bone densitometer.
Unilateral images were obtained independently for each
hindlimb inclusive of the respective tibia, femur, lumbar
spine, and pelvic anatomy in each scan; animals were
then repositioned, and scans were repeated for the contralateral limb. After image capture, regions of interest
were placed around the entire femur and lumbar spine,
and readings of bone mineral content and projected area
were determined from the relative attenuation of highand low-energy X-ray beams. The expression areal bone
mineral density (aBMD, mg/cm2) describes the distribution of bone mineral within the selected anatomy per
unit projected area. Here, we have elected to present
our data as aBMD, as this expression normalizes the
amount of bone mineral to the rate of change in bone
size (Horton et al., 2003). Densitometric values for both
femurs were averaged for each animal, while the
reported density of the lumbar spine reflects the average
value of the two views taken for each of the hindlimbs.
Before anesthetic recovery, animals were placed into a
prone position, maintaining 90 degrees flexion as
described previously, and contact radiographs were taken
with a calibration marker used to normalize images. Tibial
length was measured from digitized films as the axial distance from the tibial plateau distally to the apex of the
tibio-talar articulation (Tamurian et al., 1999), using NIH
image v1.62 (National Institutes of Health, Bethesda,
MD). Data reported are the average of three determinations for each bone measured. Coefficients of variation
were less than 0.3% for repeated measures.
Blood Collection and Metabolic Marker Assays
Blood was obtained by tail venipuncture as described
by Bober (1988) while animals were briefly anesthetized
by isofluorane inhalation. Serum was then isolated and
stored at 2808C until analysis. A two-site immunoradiometric assay was used to determine serum levels of
osteocalcin (Immutopics, San Clemente, CA), a 50 amino
acid peptide associated with osteoblastic bone formation
activity (Morris et al., 1992). An enzyme-linked immunosorbent assay (RatTRAP ELISA Kit, SBA-IDS, Fountain
Hills, AZ) was used to evaluate temporal patterns of
bone resorptive activity (Halleen et al., 2000; Alatalo
et al., 2003), as reflected by tartrate-resistant acid phosphatase isoform 5b (TRAP5b), which is secreted into the
serum by osteoclast cells actively engaged in bone
resorption. Assays were performed in duplicate for each
sample following the kit manufacturer’s protocol.
Histomorphometry and Immunohistochemistry
Forty-eight hours before being euthanized, animals
received an intraperitoneal injection of oxytetracycline
(OTC, 50 mg/kg, Phoenix Pharmaceuticals, St. Joseph,
MO) to pulse-label newly mineralizing tissue. Thirty
minutes before being euthanized, animals received an
intraperitoneal injection of 50 -bromo-2-deoxyuridine
(BrdU, 25 mg/kg, Sigma, St. Louis, MO) to label cells
engaged in DNA synthesis. Immediately after euthanasia, the proximal 1.5 cm of both tibiae were collected,
bisected sagittally, and fixed in 70% ethanol. Tissue
SKELETAL MATURATION IN JUVENILE RATS
285
Fig. 1. Measurement of daily growth rate by oxytetracycline (OTC)
migration. A: Corresponding digital images (310 magnification) of the
proximal tibial metaphysis of a 42-day-old male rat captured by epifluorescence microscopy with a UV-1a filter set (Ex. 365nm/Em. 400
bandpass) or by phase contrast microscopy. B: To facilitate measure-
ment of the daily growth rate (see also Fig. 3a, inset), regions identified as displaying OTC fluorescence in image A were superimposed
(in red). Subsequently, the average distance between these contours
were measured (arrow).
hemispheres were subsequently embedded in methylmethacrylate resin (Erben, 1997), serially sectioned at 5
mm thickness, and mounted on aminopropyltrimethoxysilane subbed slides. Six sections were selected at uniform random 80 mm thickness intervals and prepared for
either BrdU immunohistochemistry or OTC-fluorescence
microscopy. ImagePro Plus software (v4.0, Media Cybernetics, Silver Spring, MD), was used to perform all histologic analyses from digitally captured images taken at
310 magnification.
For estimation of daily growth rate, three tissue sections
were sampled as described earlier, de-plasticized in xylene,
and cover-slipped. Two corresponding digital images of
each unstained tissue section were obtained under brightfield phase contrast or UV1a epifluorescence (Ex. 350 nm/
Em. >400 nm bandpass) illumination, respectively (Fig. 1).
Subsequently, ImagePro Plus was used to merge these
images, and the distance between the metaphyseal chondro-osseous junction and the front of OTC-labeled mineralized matrix was measured as described previously
(Farnum and Wilsman, 1989; Damron et al., 2006; Horton
et al., 2006). For this technique, coefficients of variation
were less than 0.5% in repeated measurements of any
given section (e.g., investigator error) and 3–8% between
uniform random sections sampled from any tissue block
(e.g., biological variability).
Immunohistochemical labeling of BrdU incorporation
was performed following antigen retrieval as previously
described by Baroukh et al. (2000), using a mouse antiBrdU monoclonal antibody (#347580, 1:100, Becton Dickinson, San Jose, CA), and visualized through horseradish peroxidase–diaminobenzidine histochemistry (SK4100, Vector Laboratories, Burlingame, CA). An index of
proliferative activity was then calculated as outlined in
our earlier reports (Damron et al., 2006; Horton et al.,
2006). In brief, we calculated the proportion of BrdU-immunoreactive cellular profiles per total cellular profiles
in the selected sections. This proportion was then modified by application of a correction factor to account for
the probability of observing a nucleated cellular profile
in any randomly selected cellular profile observed in a
tissue section less than one cell-diameter in thickness
(Farnum and Wilsman, 1993).
Statistical Analyses
Data mean and standard deviation were calculated for
each parameter measured at each time point and plotted
against the animal age at the time of measurement using
Excel Software (Microsoft Inc., Redmond, WA). All other
statistical functions were performed using StatView
v5.0.1 software (SAS Institute, Cary, NC). Analyses of var-
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HORTON ET AL.
iance with Bonferroni-Dunn post hoc tests were performed
to identify successive periods of significant growth accumulation. Unpaired Student’s t-tests were performed to
demonstrate gender divergence at each time point, accepting differences as significant when P 0.05. Simple and
multiple regression analyses were used to assess the significance and degree of association between variables.
The measured data for body weight gain, femoral and
lumbar bone mineral accretion, and tibial elongation
were fitted to a Gompertzian growth curve of the form
described by Laird (1965a,b, 1967). This function temporally describes growth procession through successive
phases of rapid, decaying, and asymptotic growth. Within
this function, iterative regressions with exponential, logistic,
and linear models were used to estimate the age at which
transition between the respective periods would occur.
RESULTS AND OBSERVATIONS
Serial Assessment of Bone Mineral
Accrual by DXA
Measurements of bone mineral content aBMD by DXA
are shown for the femur (Fig. 2) and lumbar (L1–L4) vertebral segments (Fig. 3). Initially, bone mineral density
rapidly accrued on an exponential trajectory in both
male and female rats before decay in growth became
apparent at 78 days of age for the femur (r2 0.98; Fig.
2) or at 71 days in the lumbar spine (r2 0.97; Fig. 3).
Beyond 78 days of age, femurs from male rats had accumulated significantly greater aBMD (t-test; P 0.043)
than age-matched females. The lumbar spine of male
rats showed greater aBMD than female counterparts
only at 113 and 284 days of age (P 0.018). No statistically significant difference was demonstrated in lumbar
aBMD between sexes at any other time point.
decayed, and no statistically significant growth was
observed beyond 109 days of age in females (r2 5 0.84; P
5 0.189) and 144 days in males (r2 5 0.80; P 5 0.73)
when measured radiographically. This finding may
reflect an insensitivity to measured differences of less
than approximately 0.05 mm by this method. Thus, a
histomorphometric OTC pulse-migration study (Fig. 2a,
inset) was performed at select time points to estimate
daily growth rate with much greater resolving power
than possible by radiography.
Growth rate was measured in 42-day-old males during
the mid-exponential growth phase and found to proceed
at average rate of 240 6 5 mm/day by OTC migration
(Figs. 5, 6). Temporally significant declines in growth
rate were also observed between initial measurement
and the 71-day early- (101 6 5 mm/day) and 112-day
late- (44 6 7 mm/day) decay phases (ANOVA, P 0.002)
measurements. Tibial growth rate of animals sampled at
either early- (16 6 2 mm/day at 140 days) or late- (7 6 4
mm/day at 350 days) time points during plateau phase
were not significantly different from each other (P 5
0.2), but were both significantly reduced compared with
all previous time points (ANOVA, P 0.0001). Furthermore, regression analysis showed a very strong inverse
association (r2 > 0.99) between tibial length and growth
rate.
An index of proliferative activity of epiphyseal growth
plate chondrocytes was calculated by BrdU immunohistochemistry (Fig. 6). Proliferative activity decreased significantly with advancing age (P < 0.003). Additionally,
the proliferative index calculated from 351 day old tissues (1.51 6 1.70%) was not significantly different from
0. Regression analysis suggested an association between
OTC growth rate (r2 5 0.81) and tibial length (r2 5 0.83).
CONCLUSIONS AND DISCUSSION
Serum Markers of Osteoblast and
Osteoclast Activity
Serum markers of bone metabolic activity were
assayed at time points corresponding to the period of
significant of bone growth and mineral accrual (Fig. 4).
Serum levels of osteocalcin suggest that the rate of bone
formation decreases significantly with increasing age in
both males and females (analysis of variance [ANOVA],
P 0.016). There were no significant gender differences
at any time point (t-test, P > 0.102). Serum TRAP5b levels did not fluctuate significantly during the period
observed serially within either sex (ANOVA, P 0.182).
Gender differences were generally unremarkable for
both serum osteocalcin and TRAP5b (t-test, P > 0.206),
although there was a statistically significant difference
between sexes in TRAP5b levels noted at 56 days of age
(t-test, P 5 0.043). Regression analysis showed a positive
association between serum osteocalcin levels and BMD
(lumbar r2 5 0.74, femoral r2 5 0.71). However, TRAP5b
levels were not as closely associated with BMD at either
site (r2 < 0.41).
Serial Studies of Endochondral Elongation
Measurements taken from contact radiographs
revealed that tibiae in both male and female rats grew
at a nearly exponential rate (r2 0.91) through 64 days
of age (Fig. 2). This rate of elongation subsequently
Several growth functions have been proposed, which
are intended to describe the temporal progression of
ontogenetic processes (Kingsland, 1995). Common among
several of these formulae is the ability to derive an
inflection point from empirical data, which estimates the
age at which some process alters the trajectory of
growth from an exponential rate toward decay. We have
imputed our experimental data to a Gompertzian function of the form derived by Laird (1965a,b, 1967) and
report that the overall process of skeletal maturation
proceeds along a trajectory adequately predicted by this
function. Before the calculated inflection point, however,
we found that our data regarding tibial elongation and
bone mineral accrual fit more closely to the trajectory of
an exponential model (Figs. 2–4 dashed lines), than to
the Gompertz. Similarly, subsequent growth rate decay
and asymptotic phases were respectively found to fit
more closely to curves generated by logistic and linear
models than to the Gompertz during these phases.
Postnatal skeletal growth and maturation is a complex
process that couples endochondral elongation and mineralization to osseous modeling and re-modeling. It has
long been assumed that bone mass acquisition during
childhood and early adulthood is of paramount importance in prevention of osteoporotic bone disease later in
life (Loro et al., 2000). In humans, there appears to be a
relatively short but crucial time period during which
most significant bone mineral accrual occurs (Gilsanz
SKELETAL MATURATION IN JUVENILE RATS
Fig. 2. Femoral bone mineral density (BMD). a,b: Data points show mean (6 1 SD) femoral BMD of
male (a) and female (b) rats as determined by in vivo dual-energy X-ray absorptiometry (DXA) bone densitometry. Solid lines show Gompertzian best-fit of data, while dashed lines show extended trajectory of
the exponential growth phase.
287
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HORTON ET AL.
Fig. 3. Lumbar bone mineral density (BMD). a,b: Data points show mean (6 1 SD) lumbar BMD of
male (a) and female (b) rats as determined by in vivo dual-energy X-ray absorptiometry (DXA) bone densitometry. Solid lines show Gompertzian best-fit of data, whereas dashed lines show extended trajectory of
the exponential growth phase.
SKELETAL MATURATION IN JUVENILE RATS
289
Fig. 4. Serum markers of bone metabolic activity. Data points show mean (6 1 SD) serum level of
TRAP5b (solid line, U/L) and osteocalcin (dashed line, ng/ml).
and Nelson, 2003; Mora and Gilsanz, 2003). This period
of peak bone mineral accrual lags slightly behind the 2year period of peak longitudinal growth during puberty
(Fournier et al., 1997; Baroncelli and Saggese, 2000;
Whiting et al., 2004). The inflection points derived from
this model demonstrate that there is a temporal lag
between the processes of endochondral elongation and
mineralization and that these inflection points occur
slightly after the age at which these animals have been
reported to achieve sexual maturity. Studies of growing
mice (Eckstein et al., 2004), rabbits (Gafni et al., 2002),
and adolescent humans (Neu et al., 2001), are analogous
to our findings in rats, suggesting a general pattern of
decreased bone formation rate approaching asymptote.
Our present experiment revealed that the decline n
serum osteocalcin was positively associated with both
femoral and lumbar bone mineral accrual during
growth, while serum TRAP5b was not closely associated.
Our observation of an age-associated decline in serum
osteocalcin levels in growing rats was similar to that
reported in mice by Eckstein and colleagues (2004).
However, in the current study we did not observe a
reduction of serum TRAP5b levels in aged rats that corresponded to the reported decline in urinary markers of
bone resorption in the former study. Such disparity
between data sets may be related to species differences
between the animals used in the respective studies, or a
difference in the assay method used.
Humans experience a brief period of preadolescent
growth quiescence preceding the pubertal growth spurt,
which corresponds temporally to the initiation of sexual
maturation (Arfai et al., 2002; Braillon, 2003). This specific pattern is not observed in rats. Rather, skeletal
growth of the rat proceeds continuously through the
juvenile and prepubertal phases along an exponential
trajectory evident at birth (Laird, 1965b; Kilborn et al.,
2002), which later decays as a function of animal age
and endocrine activity. In this study, we have observed
that significant longitudinal growth enters a decay
phase at approximately 64 days of age, lagging slightly
behind the reported age at which sexual maturity is
assumed by the appearance of mature spermatozoa in
the vas deferens in male (45–55 days), or the first ovulation in female (35–40 days) rats (Ojeda and Urbanski,
1994). Although our data appear to provide a compelling
temporal correlate of skeletal and sexual maturation, our
study was not designed to relate our radiographic assays
of skeletal maturation to the processes of puberty and sexual maturation. Thus, our data do not specifically address
the commonly held notion that skeletal and sexual maturation processes are mutually responsive to endocrine
influences governed by the hypothalamo–pituitary axis
(Ojeda and Urbanski, 1994; Robson et al., 2002).
The sequential pattern of growth plate thinning and
closure is generally considered to be a very sensitive
correlate of skeletal maturity to endocrine status and
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HORTON ET AL.
Fig. 5. Tibial length and elongation. a,b: Data points show mean (6 1 SD) tibial length of male (a) and
female (b) rats. Solid lines show Gompertzian best-fit of data, whereas hatched lines show extended trajectory of the exponential growth phase. Inset a shows mean (6 1 SD) oxytetracycline (OTC) growth rate
derived from histologic analysis of age-matched male rats.
SKELETAL MATURATION IN JUVENILE RATS
291
Fig. 6. Growth plate chondrocyte proliferation. Data show the
mean (6 1 SD) proliferative index derived from immunohistochemical
labeling of bromodeoxyuridine (BrdU) incorporation by S-phase proliferative chondrocytes. Inset: Representative BrdU immunohistochemis-
try at 42 (A), 63 (B), 112 (C), 140 (D), and 350 (E) days of age; original
magnification, 310. A–D counterstained with hematoxylin; E counterstained with methyl green. Scale bar 5100 mm.
chronologic age (Zerin and Hernandez, 1991). In some
species, the epiphysis may remain ‘‘open’’ for some time
beyond the achievement of sexual maturity (Kilborn
et al., 2002). As previously demonstrated in rats by
both Trudel et al. (2001) and Roach et al. (2003) and
others, we observed histologically ‘open’ physes in rats
at 1 year of age. In departure from the former and in
agreement with the latter study, we measured no significant proliferative activity or daily growth accumulation by the proximal tibial growth plate by our pulse
labeling studies at this late time point. In addition, we
have presented data obtained by both radiologic measurement of tibial length and histomorphometric measurement of OTC-based daily growth rate, indicating
that beyond 20-weeks of age, tibial growth had declined
to a rate that produced only statistically insignificant
gains. Our inability to detect any significant elongation
in these older animals, as has been reported by others,
may reflect a limitation of sensitivity inherent in
the measurement approaches we have taken. However,
that we fail to see substantial BrdU uptake in the
growth plate and that there are few remaining chondrocytes of either proliferative or hypertrophic morphology in the growth plate of these older animals (Fig. 6E)
suggests that whatever growth accrues at these
advanced ages is not likely a product of chondrocytic
duplication and hypertrophic enlargement (Wilsman
et al., 1996). Rather, it is possible and indeed quite likely
that this residual elongation and may be the product of
some interstitial growth mechanism such as matrix secretion (Pavasant et al., 1996), rather than the product of a
persistent primary endochondral process.
It was our purpose in this study to examine skeletal
maturation during the transition from preadolescentto-adult, rather than the preceding neonatal phase. As
such, we are unable to comment on any gender or temporal patterns established during the earlier periods of
growth or on whether patterns established during this
period are analogous to those observed in humans (Gafni
et al., 2002). Second, our histomorphometric observations on the decay of longitudinal growth rate as a function of age considered only the proximal tibial growth
plate. It is widely known that various growth plates
throughout the body display different growth rates
(Wilsman et al., 1996) and that they close in a specific,
reproducible sequence (Zerin and Hernandez, 1991).
Finally, our experiment did not examine the role of endocrine influences on skeletal biology, so we are limited
solely to discussion of the temporal correspondence of
these developmental processes of maturation, rather
than any specific mechanism coordinating their progression. In the long-term, we plan to use this model to
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HORTON ET AL.
study what role that insults affecting skeletal metabolism and growth during childhood and adolescence, may
have on adult bone quality. The methodologies used to
study this progression are quite analogous to those used
in clinical practice, and thus are geared toward facilitating studies that are translational in nature.
ACKNOWLEDGMENTS
This research was conducted with support of the
David G. Murray Professor of Orthopedic Surgery
Endowment. There are no perceived conflicts of interest
to disclose regarding this study.
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