Skeletal Mechanoresponsiveness: Effects of Sex Hormones - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 223

3.2 Deletion of Estrogen Receptor b
ERbKO mice were generated later than ERaKO mice, and have revealed a
different role for this receptor than for ERa [ 70 , 81 ]. Just as in ERaKO mice, adult
female ERbKO mice are heavier with higher fat mass than their WT littermates
[ 82 , 83 ]. Since ERb is found on osteocytes and osteoblasts as well as reproductive
organs, lack of ERb affects bones, but reports have varied [ 84 ].
Long bones of growing and adult female ERbKO mice have been reported to be
longer [ 73 , 83 ] and similar to WT values [ 64 , 83 , 85 ]. Interestingly, during growth
the skeleton of ERbKO female mice appears to be adversely affected, but during
aging the trend reverses. In growing ERbKO mice, volumetric BMD (vBMD) of
the lumbar spine and distal femur was decreased compared to WT [ 82 ]. Mice
usually develop osteopenia in trabecular-rich regions with age [ 86 ], but ERbKO
mice are protected from this bone loss. At one year, trabecular density in both tibia
and femur was higher in ERbKO females than WT by pQCT [ 87 ]. This protective
effect is even more evident in cortical bone; cortical area, BMC and cortical
thickness were increased in the tibia and femur of 1-year-old female ERbKO mice
compared to WT [ 87 ].
Male ERbKO bones, in contrast, exhibit few abnormalities. Bone length, total
BMC and cortical density and area were similar in tibiae and femora from ERbKO
and WT mice [ 87 ]. Interestingly, male ERbKO male body mass and some skeletal
phenotypes are similar to female WT, suggesting a ''feminization'' of ERbKO
male bones [ 87 ].
Aside from the skeletal phenotypes, other systemic effects were present in ERbKO
mice. Reports of altered hormone levels have varied. The initial female ERbKO mouse
models did not have altered estrogen serum levels [ 73 , 87 ]. Subsequent female ERbKO
mouse models showed increased serum estrogen levels [ 82 ]. Interestingly, at 1 year of
age, ERa mRNA levels were two-fold higher in ERbKO female mice than WT
females, suggesting that ERb may suppress effects of ERa in the genome, or that ERa
compensates for the lack of ERb through a yet unknown mechanism [ 87 ].
While the in vitro response of bone cells to loading is increased in the absence
of ERb [ 20 ], the in vivo loading data for the ulnae of ERbKO mice are conflicting.
The inconsistent data may reflect differences in loading protocols or the different
genetic mutation of the ERb gene. In a mouse model with an insertional mutation
in the ERb gene, the loading-induced increase in cortical area and MAR in the
ulna was less in adult (5-months-old) female ERbKO mice compared to WT
controls [ 64 ]. In contrast, using adult (4-months-old) mice with an exon 3 deletion
in the ERb gene, MAR and BFR increased more in response to loading in the ulna
in female ERbKO mice compared to WT [ 82 ]. In the same study, male ERbKO
and WT mice responded similarly to in vivo loading [ 82 ]. Therefore, the role of
ERb is more apparent in females than males, both through phenotype and through
response to mechanical loading.