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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
"osteoporosis"
symptom
achondroplasia
adrenal incidentaloma
allergic bronchopulmonary aspergillosis
aromatase deficiency
congenital adrenal hyperplasia
cushing syndrome
cutaneous mastocytosis
dentinogenesis imperfecta
erythropoietic protoporphyria
fabry disease
familial hypocalciuric hypercalcemia
familial mediterranean fever
inclusion body myositis
kallmann syndrome
oligodontia
pyomyositis
werner syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated
