Skeletal Mechanoresponsiveness: Effects of Sex Hormones - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 221

3 Genetic Models of Sex Hormone Deficiency
Estrogen and testosterone are signaling hormones that act via estrogen receptors
(ERs) and androgen receptor (AR), respectively, located in the cytosol (Fig. 1 ). Sex
hormones are involved in reproductive signaling, but their receptors are also
expressed in bone cells (osteoblasts, osteoclasts, and osteocytes) at levels around ten
times lower than that of reproductive tissues [ 56 ]. The two known estrogen receptors
are estrogen receptor alpha (ERa) and estrogen receptor beta (ERb). When estrogen
interacts with an ER, the receptor translocates to the nucleus, phosphorylates,
dimerizes, and mediates gene transcription via classical estrogen response elements
or via direct interaction with DNA binding sites to increase cell number and activity
[ 57 ]. Androgen actions are mediated through the AR, which then dimerizes and can
regulate gene transcription through androgen response elements (AREs) although
non-genomic activities have also been implicated [ 58 , 59 ].
Both ERs and ARs have important implications in bone maintenance (Vico and
Vanacker). In 1994, a man was discovered who had an inactivating point mutation
in the ERa gene [ 60 ]. He presented with open growth plates and severe osteopo-
rosis, suggesting that ERa plays an important role in bone maturation and
homeostasis. Although not the focus of this chapter, a number of in vitro studies
subsequently demonstrated the importance of ERa in the anabolic response of bone
cells to mechanical strain [ 61 - 65 ]. (See '' Bone Cell Mechanoresponsiveness '' ,
Genetos and Jacobs.) Normally, mechanical loading enhances cell proliferation in
vitro. When the effects of ERa are blocked using selective estrogen receptor
modulators, strain-induced proliferation of osteoblast-like cells derived from rat
long bones was reduced [ 62 ]. Similarly, osteoblast-like cells from ERaKO mice
proliferated less in response to mechanical loading compared to wild type (WT)
cells [ 64 , 66 , 67 ]. Furthermore, ERa can be activated not only by estrogen, but also
by mechanical strain alone or in combination with estrogen [ 68 ]. In vitro, the effects
of loading on bone cells from ERbKO mice are opposite from those observed in
cells from ERaKO mice. Mechanical stimulation doubled proliferation of cultured
osteoblast-like cells from ERbKO mice compared to WT cells [ 64 , 66 ].
In the following sections we will review the roles of ERs and AR in bone
mechanotransduction based on in vivo studies examining ERaKO, ERbKO and
ARKO mice. The skeletal phenotype resulting from the receptor deletion will be
presented first, followed by results from controlled loading studies.
3.1 Deletion of Estrogen Receptor Alpha
The first ERaKO mice were generated in 1993 by an insertional gene mutation, but
since then improved ERaKO mice have been generated to minimize ERa protein
detection and gene expression [ 69 - 72 ]. Absence of ERa affects both reproductive
tissue and bone phenotypes in female mice. Body mass and body fat are both