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Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis.
[werner syndrome]
A
major
medical
challenge
in
the
elderly
is
osteoporosis
and
the
high
risk
of
fracture
.
Telomere
dysfunction
is
a
cause
of
cellular
senescence
and
telomere
shortening
,
which
occurs
with
age
in
cells
from
most
human
tissues
,
including
bone
.
Telomere
defects
contribute
to
the
pathogenesis
of
two
progeroid
disorders
characterized
by
premature
osteoporosis
,
Werner
syndrome
and
dyskeratosis
congenital
.
It
is
hypothesized
that
telomere
shortening
contributes
to
bone
aging
.
We
evaluated
the
skeletal
phenotypes
of
mice
with
disrupted
telomere
maintenance
mechanisms
as
models
for
human
bone
aging
,
including
mutants
in
Werner
helicase
(
Wrn
(
-
/
-
)
)
,
telomerase
(
Terc
(
-
/
-
)
)
and
Wrn
(
-
/
-
)
Terc
(
-
/
-
)
double
mutants
.
Compared
with
young
wild-
type
(
WT
)
mice
,
micro-computerized
tomography
analysis
revealed
that
young
Terc
(
-
/
-
)
and
Wrn
(
-
/
-
)
Terc
(
-
/
-
)
mice
have
decreased
trabecular
bone
volume
,
trabecular
number
and
trabecular
thickness
,
as
well
as
increased
trabecular
spacing
.
In
cortical
bone
,
young
Terc
(
-
/
-
)
and
Wrn
(
-
/
-
)
Terc
(
-
/
-
)
mice
have
increased
cortical
thinning
,
and
increased
porosity
relative
to
age-matched
WT
mice
.
These
trabecular
and
cortical
changes
were
accelerated
with
age
in
Terc
(
-
/
-
)
and
Wrn
(
-
/
-
)
Terc
(
-
/
-
)
mice
compared
with
older
WT
mice
.
Histological
quantification
of
osteoblasts
in
aged
mice
showed
a
similar
number
of
osteoblasts
in
all
genotypes
;
however
,
significant
decreases
in
osteoid
,
mineralization
surface
,
mineral
apposition
rate
and
bone
formation
rate
in
older
Terc
(
-
/
-
)
and
Wrn
(
-
/
-
)
Terc
(
-
/
-
)
bone
suggest
that
osteoblast
dysfunction
is
a
prominent
feature
of
precocious
aging
in
these
mice
.
Except
in
the
Wrn
(
-
/
-
)
single
mutant
,
osteoclast
number
did
not
increase
in
any
genotype
.
Significant
alterations
in
mechanical
parameters
(
structure
model
index
,
degree
of
anistrophy
and
moment
of
inertia
)
of
the
Terc
(
-
/
-
)
and
Wrn
(
-
/
-
)
Terc
(
-
/
-
)
femurs
compared
with
WT
mice
were
also
observed
.
Young
Wrn
(
-
/
-
)
Terc
(
-
/
-
)
mice
had
a
statistically
significant
increase
in
bone
-marrow
fat
content
compared
with
young
WT
mice
,
which
remained
elevated
in
aged
double
mutants
.
Taken
together
,
our
results
suggest
that
Terc
(
-
/
-
)
and
Wrn
(
-
/
-
)
Terc
(
-
/
-
)
mutants
recapitulate
the
human
bone
aging
phenotype
and
are
useful
models
for
studying
age-related
osteoporosis
.
Diseases
Validation
Diseases presenting
"prominent feature"
symptom
aniridia
cutaneous mastocytosis
neonatal adrenoleukodystrophy
oculocutaneous albinism
werner syndrome
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