Skeletal Mechanoresponsiveness: Effects of Sex Hormones - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 224

3.3 Deletion of Androgen Receptor
Generating ARKO mice is a genetic challenge because the AR gene is present on
the X chromosome and required for male fertility, making female generations of
ARKO mice difficult to create and therefore less studied [ 88 ]. A number of male
ARKO mouse models have been generated; this chapter will only focus on the
results in bone tissue [ 88 , 89 ].
Male ARKO mice differed phenotypically from their WT controls. During
growth body mass is lower in male ARKO mice than WT males [ 90 ]. However,
after 10 weeks of age, ARKO male mice rapidly increase mass to surpass the WT
males and eventually become obese [ 91 ]. At 8 weeks, serum testosterone levels
were lower in male ARKO mice compared to WT [ 90 , 92 ]. Cortical and trabecular
bone are both severely affected by lack of AR at 8 weeks of age. In the femur,
cross sectional area, cortical area, and cortical thickness were all lower than in
WT [ 93 ]. In both the femur and tibia, trabecular bone volume was decreased to
osteopenic levels [ 92 , 93 ]. These cortical and cancellous trends continued into
adulthood [ 94 ]. Interestingly, bone formation rate in both the tibia and femur was
increased, but it was accompanied by increased resorption rates, which exceeded
the bone formation rates and thus resulted in osteopenia [ 92 , 93 ].
Although bone resorption rates in growing male ARKO mice exceed bone
formation rates in WT mice, in vivo mechanical loading can still stimulate
bone formation [ 95 ]. The left ulnae of 5-months-old male ARKO and WT mice
were subjected to 40 cycles of loading with peak strains of 1560-1740 le [ 95 ].
Stiffness was similar for both genotypes at the start of the experiment. After 2
weeks, periosteal bone formation rates increased with loading in both genotypes,
but the change was significantly greater in ARKO mice, possibly due to a
disruption in the Wnt/b-catenin pathway, known to play a role in bone's
mechanoresponsiveness [ 96 ]. SOST, a gene that codes for sclerostin, an inhibitor
of the Wnt/b-catenin pathway, had decreased expression after mechanical loading
in WT mice, but more so in ARKO mice. In contrast, the number of sclerostin-
positive osteocytes decreased in ARKO mice after mechanical loading, but not in
WT. These data suggest a role for AR in the Wnt/b-catenin signaling pathway in
addition to ERa's hypothesized role.
To further study AR's role in bone adaptation, ARKO mice have been subjected
to both increased and decreased physical activity with different results in cortical
versus cancellous bone. In an exercise study, ARKO male mice were subjected to
voluntary exercise from age 1 to 4-months [ 94 ]. Bone turnover parameters were
lower in sedentary than exercised ARKO mice, as expected. Furthermore, tra-
becular bone mineral density, bone volume, and trabecular number were greater in
the tibiae of exercised ARKO compared to sedentary mice. However, running did
not affect cortical bone gain in exercised ARKO mice compared to sedentary mice.
In contrast, the combination of AR deficiency and hind limb unloading affected
both trabecular and cortical bone in ARKO mice, demonstrating the importance of
AR in bone maintenance especially under disuse conditions [ 97 ]. Following tail