A tissue-specific role of membrane-initiated ERα signaling for the effects of SERMs

Abstract

Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists or antagonists in a tissue-specific manner. ERs exert effects via nuclear actions but can also utilize membrane-initiated signaling pathways. To determine if membrane-initiated ERα (mERα) signaling affects SERM action in a tissue-specific manner, C451A mice, lacking mERα signaling due to a mutation at palmitoylation site C451, were treated with Lasofoxifene (Las), Bazedoxifene (Bza) or estradiol (E2), and various tissues were evaluated. Las and Bza treatment increased uterine weight to a similar extent in C451A and control mice, demonstrating mERα-independent uterine SERM effects, while the E2 effect on uterus was predominantly mERα-dependent. Las and Bza treatment increased both trabecular and cortical bone mass in controls to a similar degree as E2, while both SERM and E2 treatment effects were absent in C451A mice. This demonstrates that SERM effects, similar to E2 effects, in the skeleton are mERα-dependent. Both Las and E2 treatment decreased thymus weight in controls, while neither treatment affected the thymus in C451A mice, demonstrating mERα-dependent SERM and E2 effects in this tissue. Interestingly, both SERM and E2 treatments decreased the total body fat percent in C451A mice, demonstrating an ability of these treatments to affect fat tissue in the absence of functional mERα signaling. In conclusion, mERα signaling can modulate SERM responses in a tissue-specific manner. This novel knowledge increases the understanding of the mechanisms behind SERM effects and may thereby facilitate the development of new improved SERMs.

Membrane estrogen receptor α signaling modulates the sensitivity to estradiol treatment in a dose- and tissue- dependent manner

“…Thymus and gonadal fat were collected and weighed. Thymus weight data from the medium dose experiment has been previously published 16 . Uterus was collected and divided into halves.…”

“…In genetically modified mouse models, abrogation of mERα signaling by mutating palmitoylation site C451 in ERα results in phenotypic changes in a tissue-specific way 11 , 12 . E2 (17β-estradiol) treatment in gonadectomized mice without mERα signaling also reveals a strong tissue-dependent response of E2 13 – 16 , and this knowledge could be used for searching future therapeutic targets for disorders related to low E2 levels, such as postmenopausal osteoporosis.…”

“…For example, uterus is known to be a highly E2-sensitive organ, while trabecular bone is less sensitive 21 . The E2 treatment studies in mERα-signaling deprived mouse models have so far only investigated one E2 dose each, and the studies vary in administration route, dose, treatment length, gender and/or age 11 – 16 , 23 . Some of these studies have shown conflicting results on tissue responses to E2 treatment, however, due to the differences in study designs, it is inappropriate to directly compare E2 sensitivity in different tissues between studies.…”

Selective estrogen receptor modulators in post-menopausal osteoporosis

“…Bazedoxifene increases BMD and prevents vertebral and nonvertebral fractures [41,42] . It has similar efficacy to raloxifene in decreasing fracture risk but has fewer side effects than raloxifene, exerting no negative actions at the level of breast tissue and endometrium [43] .…”

“…It has similar efficacy to raloxifene in decreasing fracture risk but has fewer side effects than raloxifene, exerting no negative actions at the level of breast tissue and endometrium [43] . Gustafsson et al investigated the relationship between mER-α signaling and the action of bazedoxifene and lasofoxifene (other third-generation SERMs) in C451A mice, which, due to a mutation on the palmitoylation site, lack mER-α signaling [42] . Treatment with the two SERMs resulted in increased cortical thickness in vertebrae and cortical bone in the femur similarly to 17-β-estradiol in control mice, whereas no effect was recorded in C451A mice.…”