Deletion of estrogen receptors reveals a regulatory role for estrogen receptors-β in bone remodeling in females but not in males

Sims, Natalie A.; Dupont, Sonia; Krust, Andrée; Clément-Lacroix, Philippe; Minet, Dominique; Resche-Rigon, Matthieu; Gaillard-Kelly, Martine; Baron, Roland

doi:10.1016/s8756-3282(01)00643-3

Cited by 317 publications

(312 citation statements)

References 32 publications

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“…Interestingly, studies from our laboratory indicate that E 2 induces the expression of TIEG in OB [7]. Estrogen receptor α and β double knockout mice display profound decreases in trabecular bone volume only in female animals with no differences in male mice [37]. The bone phenotype of these mice closely resembles that of our TIEG -/-mice suggesting that TIEG may play an important role in mediating the effects of E 2 in bone.…”

Section: Discussionsupporting

confidence: 55%

TIEG-null mice display an osteopenic gender-specific phenotype

Hawse

Iwaniec

Bensamoun

et al. 2008

Bone

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TGFβ Inducible Early Gene-1 (TIEG) was originally cloned from human osteoblasts (OB) and has been shown to play an important role in TGFβ/Smad signaling, regulation of gene expression and OB growth and differentiation. To better understand the biological role of TIEG in the skeleton, we have generated congenic TIEG-null (TIEG -/-) mice in a pure C57BL/6 background. Through the use of DXA and pQCT analysis, we have demonstrated that the femurs and tibias of two-month-old female TIEG -/-mice display significant decreases in total bone mineral content, density, and area relative to wild-type (WT) littermates. However, no differences were observed for any of these bone parameters in male mice. Further characterization of the bone phenotype of female TIEG -/-mice involved mechanical 3-point bending tests, micro-CT, and histomorphometric analyses of bone. The 3-point bending tests revealed that the femurs of female TIEG -/-mice have reduced strength with increased flexibility compared to WT littermates. Micro-CT analysis of femurs of two-month-old female TIEG -/-mice revealed significant decreases in cortical bone parameters compared to WT littermates. Histomorphometric evaluation of the distal femur revealed that female TIEG -/-mice also display a 31% decrease in cancellous bone area, which is primarily due to a decrease in trabecular number. At the cellular level, female TIEG -/-mice exhibit a 42% reduction in bone formation rate which is almost entirely due to a reduction in double labeled perimeter. Differences in mineral apposition rate were not detected between WT and TIEG -/-mice. Taken together, these findings suggest that female TIEG -/-mice are osteopenic mainly due to a decrease in the total number of functional/mature OBs.

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Section: Discussionsupporting

confidence: 55%

TIEG-null mice display an osteopenic gender-specific phenotype

Hawse

Iwaniec

Bensamoun

et al. 2008

Bone

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“…(28) Estrogen and estrogen receptor alpha activation after aromatization of androgens play a role in cortical bone development as well, as illustrated by the cortical phenotype in AR-ERa double-knockout mice. (24,34) Finally, more indirect AR-regulated mechanisms-including an impact on growth hormone secretion and its actions-may also be involved in the development of male cortical bone structure, a concept supported by observations of less cortical bone changes in male orchidectomized growth hormone receptor knockout mice. (35) In conclusion, in male mice, AR activation in osteocytes contributes to the decrease of trabecular bone but appears less or not important for the development of cortical bone during puberty.…”

Section: Discussionmentioning

confidence: 96%

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

Sinnesael

Claessens

Laurent

et al. 2012

Journal of Bone and Mineral Research

102

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Androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling has been mainly attributed to osteoblasts. Although osteocytes have emerged as key regulators of bone remodeling, the influence of sex steroids on these cells has been poorly studied. We aimed to investigate the role of AR signaling, specifically in osteocytes using the Cre/LoxP system in male mice (driven by dentin matrix protein 1 [ocy-ARKOs]). Osteocyte fractions of control (AR(ex2)/Y) and ocy-ARKO (ARflox(ex2)/Y; DMP1-cre) mice isolated through sequential collagenase digestion showed increasing AR expression toward the mature osteocyte fraction of control males compared with the more immature fractions, whereas this was reduced by >80% in ocy-ARKO osteocytes. The skeletal phenotype of mutant mice was further assessed by histomorphometry and quantitative micro-computed tomography at 12 and 32 weeks of age. Ocy-ARKOs had significantly lower trabecular bone volume and number in femora and tibias at 32 weeks as well as decreased trabecular number in the L 5 vertebra at 12 weeks. Biomechanical testing showed that ocy-ARKO femora were also stiffer and required a lower ultimate force to induce failure at 32 weeks. However, femoral cortical structure was not significantly different at any time point. The absence of AR in osteocyte also did not appear to affect trabecular bone formation nor its response to mechanical loading. In conclusion, selective inactivation of the AR in osteocytes of male mice accelerates age-related deterioration of skeletal integrity. These findings provide evidence for a direct role of androgens in the maintenance of trabecular bone through actions of the AR in osteocytes. ß

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“…Moreover, we [13] and others [19] have shown that while cortical bone contains predominantly (or exclusively) ERα, trabecular bone contains mostly ERβ, with lessor amounts of ERα. In addition, there is now increasing evidence that, at least in mice, while E utilizes both ERα and ERβ signaling in trabecular bone in females, ERβ appears to play virtually no role in mediating E effects on bone in males [20]. Thus, loss of SRC-1 (which may interact predominantly with ERβ or ERα/β in bone cells) [18] would be expected to have a much greater impact on E action in female as compared to male mice, as demonstrated by the present studies.…”

Section: Discussionmentioning

confidence: 99%

The skeletal response to estrogen is impaired in female but not in male steroid receptor coactivator (SRC)-1 knock out mice

Mödder

Sanyal

et al. 2008

Bone

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Estrogen (E) is critical for the maintenance of bone mass in both female and male mice and steroid receptor coactivator (SRC)-1 has been shown to be important for mediating E effects on bone, at least in female mice. In the present study, we defined the skeletal phenotype of male SRC-1 knock out (KO) mice and compared it with their female littermates. Further, to determine the role of SRC-1 in mediating effects of E on bone in male mice, we examined the skeletal effects of gonadectomy (gnx) with or without E replacement in male mice and placed these findings in the context of our previous studies in female SRC-1 KO mice.Analysis of a large group of male (WT, n=67; SRC-1 KO, n=56) and female (WT, n=66; SRC-1 KO, n=70) mice showed a significant decrease in trabecular volumetric bone mineral density (vBMD) in SRC-1 KO mice compared to their WT littermates in both genders (male SRC-1 KO, 275 ± 3 vs WT, 295 ± 3 mg/cm 3 , P<0.001; female SRC-1 KO, 210 ± 2 vs WT, 221 ± 2 mg/cm 3 , P<0.001). Following gnx and E replacement (10 μg/kg/d), we previously demonstrated that SRC-1 KO female mice have a defect in E action in trabecular, but not in cortical bone. In contrast, we now demonstrate that the same dose of E administered to gnx'd male SRC-1 KO mice was sufficient to prevent trabecular bone loss in these mice. For example, in WT female mice, gnx followed by E replacement maintained spine BMD (1.2 ± 3.4% vs baseline) as compared to gnx without E replacement (−12.7 ± 2.6%, P<0.001 vs sham); this effect of E was absent in SRC-1 KO female mice. By contrast, the identical dose of E was equally effective in maintaining spine BMD in E-treated gnx'd male WT (−5.2 ± 5.1% vs baseline) and male SRC-1 KO (−5.4 ± 5.3%) mice, respectively, as compared to gnx'd mice without E treatment (WT, −17.6 ± 2.5%, P=0.02; SRC-1 KO, −28.6 ± 2.6%, P<0.001 vs sham). E treatment was effective in suppressing cancellous bone turnover in both gnx'd WT and SRC-1 KO male mice as determined by significant reductions in osteoblast and osteoclast numbers; however, in female mice, E treatment only suppressed bone turnover in WT but not in SRC-1 KO mice.Collectively, these findings demonstrate that loss of SRC-1 results in trabecular osteopenia in male and female mice, but in contrast to female mice, this is not due to any detectable resistance to E action in trabecular bone in male SRC-1 KO mice.

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Deletion of estrogen receptors reveals a regulatory role for estrogen receptors-β in bone remodeling in females but not in males

Cited by 317 publications

References 32 publications

TIEG-null mice display an osteopenic gender-specific phenotype

TIEG-null mice display an osteopenic gender-specific phenotype

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

The skeletal response to estrogen is impaired in female but not in male steroid receptor coactivator (SRC)-1 knock out mice

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