Phosphorylation of S122 in ERα is important for the skeletal response to estrogen treatment in male mice

Abstract

Estrogen receptor alpha (ERα) signaling has beneficial skeletal effects in males. ERα signaling also affects other tissues, and to find bone-specific treatments, more knowledge regarding tissue-specific ERα signaling is needed. ERα is subjected to posttranslational modifications, including phosphorylation, which can influence ERα function in a tissue-specific manner. To determine the importance of phosphorylation site S122 (corresponding to human ERα site S118) for the skeleton and other tissues, male mice with a S122A mutation were used. Total areal bone mineral density was similar between gonadal intact S122A and WT littermates followed up to 12 months of age, and weights of estrogen-responsive organs normalized for body weight were unchanged between S122A and WT males at both 3 and 12 months of age. Interestingly, 12-month-old S122A males had decreased body weight compared to WT. To investigate if site S122 affects the estrogen response in bone and other tissues, 12-week-old S122A and WT males were orchidectomized (orx) and treated with estradiol (E2) or placebo pellets for four weeks. E2 increased cortical thickness in tibia in both orx WT (+ 60%, p < 0.001) and S122A (+ 45%, p < 0.001) males. However, the E2 effect on cortical thickness was significantly decreased in orx S122A compared to WT mice (− 24%, p < 0.05). In contrast, E2 affected trabecular bone and organ weights similarly in orx S122A and WT males. Thus, ERα phosphorylation site S122 is required for a normal E2 response specifically in cortical bone in male mice, a finding that may have implications for development of future treatments against male osteoporosis.

Estrogen Receptor Alpha Splice Variants, Post-Translational Modifications, and Their Physiological Functions

“…Postmenopausal women often experience bone loss and increased risk of osteoporosis [ 82 ]. The mutant S122A ERα mice also display normal mineral density and skeletal architecture of the bones in both females and males [ 65 , 66 ]. The mutant S122A ERα mice show sexually dimorphic tissue-specific genetic effects.…”

“…The mutant female mice show significantly more fat accumulation, increased adipocyte size, and body weight gain associated with an increase in fat mass composition [ 65 ]. On the other hand, while mutant S122A ERα male mice show normal sex steroid hormone levels, they show significantly lower body weight associated with lower fat mass after 9 months of age [ 66 ]. Since estrogens themselves facilitate S118 phosphorylation of human ERα [ 63 ], this sex differences of genetic effects may be due to the ligand abundance in females.…”