Critical Role of Estrogens on Bone Homeostasis in Both Male and Female

[madman]

Abstract: Bone is a multi-skilled tissue, protecting major organs, regulating calcium phosphate balance, and producing hormones. Its development during childhood determines height and stature as well as resistance against fracture in advanced age. Estrogens are key regulators of bone turnover in both females and males. These hormones play a major role in longitudinal and width growth throughout puberty as well as in the regulation of bone turnover. In women, estrogen deficiency is one of the major causes of postmenopausal osteoporosis. In this review, we will summarize the main clinical and experimental studies reporting the effects of estrogens not only in females but also in males, during different life stages. Effects of estrogens on bone involve either Estrogen Receptor (ER)α or ERβ depending on the type of bone (femur, vertebrae, tibia, mandible), the compartment (trabecular or cortical), cell types involved (osteoclasts, osteoblasts, and osteocytes), and sex. Finally, we will discuss new ongoing strategies to increase the benefit/risk ratio of the hormonal treatment of menopause.





1. Introduction

Far from inert, bone is a highly dynamic tissue undergoing constant remodeling regulated by numerous parameters and, among others, estrogens are of major importance. Estrogens are steroidal compounds derived from cholesterol. There are four identified estrogens: 17β-estradiol (E2), the most powerful and well known, estrone (E1) produced during menopause, estriol (E3) released during pregnancy by the placenta, and estetrol (E4) synthesized by the fetal liver [1]. In women, E2 is synthesized in the ovaries from puberty to menopause. E2 is responsible for the development of primary and secondary sexual characteristics in women but it is also produced in men via aromatization of testosterone in the testes (20%) and peripheral tissues (80%) [2]. It is now admitted that estrogens are key regulators of bone remodeling in both sexes [3]. Although its multifactorial origin is not quite fully elucidated (direct and indirect effects of pubertal sexual steroids, the role of autosomal genes), sexual dimorphism of the skeleton mass and architecture is well known: men have wider long bones than women and their vertebrae have a higher bone volume and thus a higher trabecular bone mineral density (BMD). The review aims to describe bone turnover regulation by estrogens and their receptors and the main differences and their common characteristics in both females and males.


1.1. Bone Physiology
1.2. Bone Cells
1.3. Bone Modeling and Remodeling




2. Skeletal Evolution throughout Life

2.1. Skeletal Development
2.2 Skeletal Maintenance
2.3. Pregnancy and Lactation
2.4. Skeletal Involution
2.5. Sex Steroid Deficiency
2.6 Aging



3. Roles of Estrogen Receptors

3.1. Estrogen Receptors
3.2. Estrogen Receptors in Bone Cells
3.3. Nuclear vs. Non-Nuclear Erα-Mediated Pathways
3.4. Selective Estrogen Receptor Modulators
3.5. Mechanical Loading





4. Conclusions

In the last ten years, tremendous advances have been made in the knowledge of estrogens and estrogen receptor function in bone but also in other tissues. The progress in genetic mouse models and pharmacological engineering has allowed us to begin to decipher mechanisms of actions of ERs and should pave the way to optimize selective ER modulation.

 

[madman]

Figure 1. Roles of estrogen in women and men throughout life. (E2: 17β-estradiol).

 

[madman]

Figure 2. Regulation of bone metabolism by estrogen receptors, cellular and molecular aspects. Estrogen’s protective effects on trabecular and cortical bone are mainly mediated by Estrogen Receptor α (ERα) in both females and males, while ERβ only plays a minor role in females and none in males. ERα belongs to the nuclear receptor superfamily and exerts its transcriptional activity through two activating functions (AFs), AF1 and AF2. Both AF1 and AF2 functions are necessary to mediate estrogen effects, whereas, in the cortical compartment, only AF2 function is necessary for females and males. Genetic murine models have allowed the study of the role of ERα in bone cells (osteoclasts, osteoblasts, and osteocytes). For each bone compartment and sex, the cell types involved in estrogen’s protective effects are indicated. A red box highlights essential ERα subfunctions in each cell type, whereas a red X indicates the dispensable ERα subfunction. Figure 2. Regulation of bone metabolism by estrogen receptors, cellular and molecular aspects. Estrogen’s protective effects on trabecular and cortical bone are mainly mediated by Estrogen Receptor α (ERα) in both females and males, while ERβ only plays a minor role in females and none in males. ERα belongs to the nuclear receptor superfamily and exerts its transcriptional activity through two activating functions (AFs), AF1 and AF2. Both AF1 and AF2 functions are necessary to mediate estrogen effects, whereas, in the cortical compartment, only AF2 function is necessary for females and males. Genetic murine models have allowed the study of the role of ERα in bone cells (osteoclasts, osteoblasts, and osteocytes). For each bone compartment and sex, the cell types involved in estrogen’s protective effects are indicated. A red box highlights essential ERα subfunctions in each cell type, whereas a red X indicates the dispensable ERα subfunction.

 

[madman]

Table 1. ERα role in bone cells and the impact of its selective deletion in trabecular and cortical bone compartments in female and male mice.

 

[madman]

Table 2. Genetic and pharmacological approaches to study the roles of ERs and their subfunctions in bone tissue regulation.