## 3 Estrogen Receptors
### Role of ER\(\alpha\) in Bone  
ER\(\alpha\) is highly expressed in bone and most of the effect of estrogen has been attributed to activity mediated through this receptor. This was proven when ovariectomized (OVX) ER\(\alpha^{-/-}\) female mice and orchicectomized (ORX) ER\(\alpha^{-/-}\) male mice did not respond to exogenous estrogen [44; 45; 46; 47]. Studying the effect of ER\(\alpha\) in bone using a global knockout approach (ER\(\alpha^{-/-}\)) gives a general idea of what its role might be. However, this approach has proven to have the downfall that alters other hormone levels. ER\(\alpha^{-/-}\) mice show a 10-fold increase in estradiol and a 5-fold increase in testosterone levels, as well as altered growth factors such as IGF-1 [44]. This alteration can lead to misinterpretation of the role and importance of the estrogen receptors in bone. One way to overcome this pitfall is using the LoxP/Cre system. In the last five years, two papers have reviewed the different bone-targeted conditional ER knockout mouse models. [PERSON] and [PERSON] (2016) outlined the different knockout mouse models of ER\(\alpha\) and ER\(\beta\) (global and tissue-specific knockouts) [48] and [PERSON] and [PERSON] (2017) reviewed the different conditional ER\(\alpha\) mice knockouts reported with a summary of their response to mechanical loading [49]. In summary, deletion of ER\(\alpha\) in osteoblast progenitors and precursors using either Prx-1 or OSx-1 Cre models lead to the reduced cortical thickness and decrease bone mineral density (BMD) in females until 28 weeks of age. Male ER\(\alpha\)/f;Prx1-cre mice also had lowered femoral BMD and decreased cortical thickness up to 8 weeks of age; however, this difference was no longer presented in 18-week-old male ER\(\alpha\)/f;Prx1-cre mice. When ER\(\alpha\) was deleted in osteoblast precursors using the 2.3 kb Col1a1 Cre mouse model, there was no difference between control and conditional knockout in cortical or trabecular bone in either sex [50]. Deletion of ER\(\alpha\) in mature osteoblasts using the Osteocalcin Cre mouse model shows a decrease in both cortical and trabecular bone parameters in young female mice, 3.5-month-old, and no difference in young males. However, at 6 months of age, male knockout had lowered trabecular bone volume [51]. Deletion of ER\(\alpha\) in osteocytes using the Dmp-1 Cre led to a decrease in trabecular bone mass in male mice and no change in cortical bone mass in either male or female [52]. These results were in part contrary to those reported by [PERSON] et al. (2104) where authors observed changes in trabecular parameters in female but not male mice; and like previously reported, no changes in cortical bone [53]. Deletion of ER\(\alpha\) in osteoclast precursors using the LysM Cre mouse model shows no changes in the cortical bone at 3 months of age. However, trabecular bone mass was decreased at 6 months of age in females. Unfortunately, males were not studied in this paper. Deletion of ER\(\alpha\) in mature osteoclasts using the Cathepsin-k Cre mouse model showed an increase in bone resorption resulting in decreased trabecular bone in females but not males [54].