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suspension for up to 2 weeks, 2-months old male ARKO mice showed rapid bone
loss, with a 70% decrease in trabecular volume in the hindlimbs [
97
]. Trabecular
bone volume decreased in both ARKO and WT mice, but the loss was greater in
ARKO mice. Cortical thickness and bone area were decreased in ARKO mice after
tail suspension, but not in WT. These exercise studies indicate that AR deletion
does not prevent bone adaptation to mechanical loading, but that decreased
physical activity in the absence of AR may be more detrimental to bone than in
mice with an intact AR.
4 Summary and Conclusions
The role of sex hormones in bone mechanotransduction has been studied in vivo
through two different approaches in rodents: surgical models of sex hormone
deficiency and genetic knockout models. The former removes circulating
bioavailable estrogen but leaves receptors and signaling pathways intact; the latter
approach targets specific components of the signaling pathway, primarily the sex
hormone receptors to date. Surgical models combined with either exercise or
applied loading demonstrate that loading can overcome the bone loss resulting
from sex hormone withdrawal. This work has focused primarily on cancellous
bone loss, but cortical effects are also present. Results comparing different loading
protocols show that not all interventions are equally successful. Particular aspects
of the loading protocol may be critical to evoking a response including moderate
intensity and duration of exercise. The responses to loading include both inhibiting
the resorption activated by sex hormone deficiency and activating bone formation.
An important limitation of this work is the lack of Haversian remodeling in
rodents, which may produce different adaptive responses in larger animal models.
From these studies, circulating estrogen does not appear to be required for the
anabolic skeletal response to exercise or applied mechanical loading.
Mechanistically, genetic models that remove estrogen or androgen receptors
provide a tremendous opportunity to understand the signaling contributions of sex
hormones in mechanotransduction. Based on genome-wide removal of estrogen
receptors in the mouse, the ERs play important roles in both cancellous and
cortical mechanotransduction. In experiments with altered mechanical loading,
the absence of ERs is more severe than the absence of circulating estrogen. This
result likely reflects the multiple signal pathways to which ERs contribute in
addition to classical estrogen signaling [
19
,
98
,
99
]. Their precise roles will be
elucidated as more in vivo data become available for individual cell types and
specific signaling pathways. Early data suggest a role for ERa in multiple
key pathways that control bone remodeling and adaptation. Future tissue-
specific knockouts aimed at isolating the effects of estrogen on individual cell
populations will provide valuable information about the role of sex hormones
in mechanotransduction.
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