Biomedical Engineering Reference
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increased due to decreased estrogen action, similar to what results when estrogen
is depleted by OVX in mice [
73
]. Deletion of ERa reduces uterine weight com-
pared to wild type (WT) mice [
74
]. Long bones are shorter in female ERaKO mice
[
64
,
74
] and correlated with decreased serum levels of IGF-1 [
73
,
74
]. Despite
shorter bone lengths, the ERaKO female skeleton is more mineralized in some
locations. In the proximal tibia, trabecular BMD was increased in growing female
ERaKO mice and even more so in young adult mice; cortical BMD and thickness
in the tibia were also increased in both growing and skeletally mature ERaKO
females compared to WT [
73
]. In the ulna, cortical area was increased, but cortical
stiffness was similar between genotypes [
64
]. However, overall BMC was
unchanged in ERaKO females compared to WT mice [
73
]. ERa plays a critical
role in bone properties of female mice, but higher levels of estrogen and testos-
terone along with lower levels of osteocalcin found in these knockout mice may
indicate compensatory mechanisms including estrogen acting via ERb [
69
,
73
].
As in female mice, in male mice the absence of ERa adversely affects both
cortical and cancellous bone from puberty onwards, characterized by shorter bone
lengths, smaller cortical area and decreased trabecular density compared to WT
males [
75
,
76
]. Despite bone phenotypic differences found in male ERaKO mice,
their response to mechanical loading has not been extensively studied.
Non-invasive in vivo loading has given further insight to the role of ERa in
bone mechanotransduction. Under normal circumstances, in vivo mouse ulnar and
tibial loading increases bone formation and BMC of loaded limbs compared to
contralateral control limbs of mice [
40
,
77
-
79
]. In ERaKO female mice, this
response is severely attenuated. The first reported in vivo loading of female
ERaKO mice loaded the ulna of 20-24 week-old female mice [
67
]. After 2 weeks,
cortical area in the midshaft of the ulna of WT mice increased 8%, but in the
ERaKO mice, cortical area increased only 2.4%. In a subsequent ulnar loading
experiment, cortical area increased three-fold less in ERaKO mice compared to
WT mice after two weeks of loading [
64
]. The increased area was primarily due to
periosteal expansion (80%) with a smaller contribution from endosteal bone for-
mation. In addition, MAR and MS increased less with mechanical loading in
ERaKO than in WT.
In vivo loading studies show that female ERaKO mice did not exhibit the same
anabolic response to controlled mechanical loading as WT mice. In a unique
examination of the genetic profile of bone cells from loaded and non-loaded tibiae
from ERaKO, OVX, and WT female mice, the right tibiae were loaded for 60
cycles at 2 Hz, with peak strains at the midshaft of 1300 le [
80
]. At 3, 8, 12 and
24 h after loading, loaded limbs of WT mice had greater differential response to
loading than either OVX WT or ERaKO mice when assessed by microarray and
qRT-PCR. For example, at the 3-h time point, only 26 genes were differentially
regulated in the ERaKO mice, compared with 642 for WT mice. These data give
insight to ERa's critical role in mechanotransduction signaling and gene expres-
sion.
ERa has
been
linked
to
a
number
of
mechanotransduction
signaling
pathways, including Wnt/b-catenin, IGF-1, and PTH [
19
].
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