Respective role of membrane and nuclear estrogen receptor (ER) α in the mandible of growing mice: Implications for ERα modulation

Abstract

Estrogens play an important role in bone growth and maturation as well as in the regulation of bone turnover in adults. Although the effects of 17β-estradiol (E2) are well documented in long bones and vertebrae, little is known regarding its action in the mandible. E2 actions could be mediated by estrogen receptor (ER) α or β. ERs act primarily as transcriptional factors through two activation functions (AFs), AF1 and AF2, but they can also elicit membrane-initiated steroid signaling (MISS). The aim of the present study was to define ER pathways involved in E2 effects on mandibular bone. Using mice models targeting ERβ or ERα, we first show that E2 effects on mandibular bone are mediated by ERα and do not require ERβ. Second, we show that nuclear ERαAF2 is absolutely required for all the actions of E2 on mandibular bone. Third, inactivation of ERαMISS partially reduced the E2 response on bone thickness and volume, whereas there was no significant impact on bone mineral density. Altogether, these results show that both nuclear and membrane ERα are requested to mediate full estrogen effects in the mandible of growing mice. Finally, selective activation of ERαMISS is able to exert an effect on alveolar bone but not on the cortical compartment, contrary to its protective action on femoral cortical bone. To conclude, these results highlight similarities but also specificities between effects of estrogen in long bones and in the mandible that could be of interest in therapeutic approaches to treat bone mass reduction. © 2018 American Society for Bone and Mineral Research.

Critical Role of Estrogens on Bone Homeostasis in Both Male and Female: From Physiology to Medical Implications

“…In contrast, ERβ −/− mice had a similar response to E2 as WT [ 76 ], showing the prominent role of ERα in bone responses to estrogen in both males and females, while ERβ only has a minor protective role in females and none in males [ 75 , 76 ] ( Figure 2 ). As in long bones and vertebrae, ERα is also necessary for E2’s protective effects in the mandible at alveolar, cortical and trabecular sites, whereas ERβ is dispensable [ 77 ]. ERαβ −/− mice, allowing the study of the possible compensatory role of one ER or the other in single-gene KO models (ERα −/− and ERβ −/− ), exhibit a similar bone phenotype to ERα −/− mice, showing that ERβ is not sufficient to compensate for ERα actions in ERα −/− mice and that ERα is truly the central actor in estrogen osteoprotective effects [ 76 ].…”

“…In bone tissue, ERαAF1 is necessary to mediate E2’s protective effects on trabecular bone in both females and males but is only partly necessary in the cortical compartment. ERαAF2 is necessary in both the cortical and trabecular compartment to elicit full E2 effects in vertebrae and femurs in both genders; in the mandible, E2’s effects on alveolar, trabecular and cortical compartments are also mediated by ERαAF2 when a dose effect can be studied precisely thanks to an appropriate pellet to deliver accurate E2 doses [ 77 , 98 , 99 , 100 ] ( Table 2 , Figure 2 ).…”

“…Moreover, ERα-MISS seems to impact osteoblasts but not the osteoclast lineage in response to E2 [ 102 ]. In the mandible, bone response to E2 treatment is slightly but significantly reduced in alveolar, trabecular and cortical compartments [ 77 ]. These results show that mERα is necessary to elicit full E2 bone-protective effects.…”

“…However, it does not seem to have effects on vertebral trabecular bone in either female or male mice [ 101 , 119 ]. In the mandible, EDC increases alveolar bone mass but has no effects on trabecular and cortical bone [ 77 ]. More recently, PaPEs originating from the rearrangement of E2 steroidal structure have been developed.…”

Estrogen signaling impacts temporomandibular joint and periodontal disease pathology

“…In the same study, there was no significant evidence to suggest that ERα played a major role in age-related TMJ growth and/or degeneration in older mice. Further in mandibular condylar bone, estrogen effects of mandibular bone density were dependent on ERα nuclear signaling and did not require ERβ signaling [70]. Figure 1 provides a summary of the general effects of estrogen on the disc and condylar fibrocartilage.…”