Female Estrogen Receptor β−/− Mice Are Partially Protected Against Age-Related Trabecular Bone Loss

Windahl, Sara H; Hollberg, Karin; Vidal, Olle; Gustafsson, Jan‐Åke; Ohlsson, Claes; Andersson, Göran

doi:10.1359/jbmr.2001.16.8.1388

Cited by 129 publications

(104 citation statements)

References 43 publications

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“…Jarred et al (2002) concluded that ER is the predominant receptor mediating the mitogenic actions of estrogen in the mouse prostate, although they indicated that a role for ER remained to be defined. There is also evidence from studies on trabecular bone that ER acts in a repressive manner, possibly by counteracting the stimulatory action of ER on bone formation (Windahl et al 2001). Recently, Liu et al (2002) described direct evidence for opposing actions of ER and ER on cyclin D1 gene expression in HeLa cells.…”

Section: Folliculogenesismentioning

confidence: 99%

Estrogen actions in the ovary revisited

Britt¹,

Findlay²

2002

Journal of Endocrinology

160

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Estrogens are synonymous with fertility and infertility in mammals. Our knowledge of the biological actions of estrogens, however, is incomplete. Three recent developments have thrown new light on the actions of estrogens in mammalian reproduction that will lead to a greater understanding of their functions. They are (a) the identification of a second estrogen receptor, called ER , (b) the identification of ligand-specific ER coactivators and (c) mouse models with targeted disruption of the genes encoding both ER and the aromatase enzyme. These models provide for the first time animals which are either unable to respond to endogenous or exogenous estrogens (ER 'knockouts'), or can respond to exogenous estrogen but do not make endogenous estrogen (aromatase 'knockout' or ArKO). Furthermore, the ArKO mouse has provided a model to study the effects on the ovary of exogenous estrogens of plant and synthetic origin that are of clinical relevance. The data show that estrogens are essential for fertility but not for survival after birth or for the formation of the reproductive tract. This commentary focuses on the roles of estrogen in folliculogenesis and in the maintenance of the ovarian somatic cell phenotype in the mouse. We also hypothesize that the ER and ER may subserve the proliferative and differentiative actions of estrogen, respectively, within a follicle. In summary, estrogen is obligatory for normal folliculogenesis beyond the antral stage and for the maintenance of the female phenotype of the somatic cells within the ovaries. This clearly demonstrates a major role for sex steroids in somatic cell differentiation in the gonads of eutherian mammals and challenges the central paradigm that the ovary is the default gonad, arising due to the absence of testicular defining signals. Evidence is also provided for the plasticity of the adult female gonad. Understanding the mechanisms of estrogen actions will provide an insight into the regulation of reproductive disorders afflicting women today, notably ovarian dysfunction and the menopause.

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Section: Folliculogenesismentioning

confidence: 99%

Estrogen actions in the ovary revisited

Britt¹,

Findlay²

2002

Journal of Endocrinology

160

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“…Both receptor subtypes have been demonstrated in the bones of immature rats and osteoblast cell lines (10)(11)(12)(13). Whether the bones of adult rats express both or only the ERa subtype is controversial (14,15). It appears that it is primarily the osteoblast cell line that expresses the ER of the a-subtype (10 -12, 14).…”

Section: Introductionmentioning

confidence: 99%

“…Many of these effects are mediated by a stimulation of osteoblast IGF-I production (21,22). The question as to whether or not osteoclasts are estrogen receptive and, if so, which ER type is being expressed, is much less clear (11,14,15). The effects of estrogens on tartrate-resistant acid phosphatase (TRAP), an osteoclast product, have been described which, however, could be indirectly exerted via paracrine mechanisms, through factors released by osteoblasts.…”

Section: Introductionmentioning

confidence: 99%

Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: comparison with estradiol-17beta

Seidlová-Wuttke

Hesse²,

Jarry³

et al. 2003

European Journal of Endocrinology

123

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Objective: Some phytoestrogens are believed to have selective estrogen receptor modulator (SERM) activity with no action in the uterus but beneficial effects in the hypothalamo/pituitary unit and in the bone and are presently the focus of clinical interest. In the present experiments, the effects of the clinically used Cimicifuga racemosa (CR) extract BNO 1055 in the uterus, in the bone and on serum luteinizing hormone (LH) were compared with the effects of estradiol-17b (E 2 ) under acute and chronic conditions in ovariectomized rats. Methods: Ovariectomized rats were treated either acutely (6 h) or chronically (3 months) with E 2 or the CR extract. Gene expression of some estrogen-regulated genes in the metaphysis of the tibia and the uterus was determined. Furthermore, bone mineral density was measured by quantitative computer tomography. Results: When given acutely, both E 2 and the CR extract inhibited LH secretion and slightly stimulated gene expression of IGF-I, collagen-1a1, osteoprotegerin and osteocalcin (all osteoblast products), and of tartrate-resistant acid phosphatase (TRAP, an osteoclast product) in the metaphysis of the femur. While E 2 stimulated uterine weight and expression of progesterone receptor (PR), the complement protein (C3) and IGF-I genes, and inhibited gene expression of the estrogen receptor b (ERb) in the uterus, no such effect was observed under acute CR treatment. After chronic application with pelleted food over 3 months E 2 had profound effects in the uterus on weight and gene expression (ERb, PR, C3 and IGF-I) which were not seen in the CR-treated animals. Within 3 months after ovariectomy, control rats had lost more than 50% of the metaphyseal bone mass of the tibia, an effect prevented by E 2 and partially by CR supplementation.

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“…The biological effects of estradiol (E2) are mainly mediated by the nuclear estrogen receptors (ERs), ERα encoded by the Esr1 gene, and ERβ encoded by the Esr2 gene. The bonesparing effect of estrogen in both males and females is primarily mediated via ERα (6)(7)(8), although the effect of ERα activation in bone might be slightly modulated by ERβ in female mice (9)(10)(11)(12).…”

mentioning

confidence: 99%

Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice

Windahl

Börjesson

Farman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

120

113

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The bone-sparing effect of estrogen in both males and females is primarily mediated via estrogen receptor-α (ERα), encoded by the Esr1 gene. ERα in osteoclasts is crucial for the trabecular bonesparing effect of estrogen in females, but it is dispensable for trabecular bone in male mice and for cortical bone in both genders. We hypothesized that ERα in osteocytes is important for trabecular bone in male mice and for cortical bone in both males and females. Dmp1-Cre mice were crossed with ERα flox/flox mice to generate mice lacking ERα protein expression specifically in osteocytes (Dmp1-ERα −/− ). Male Dmp1-ERα −/− mice displayed a substantial reduction in trabecular bone volume (−20%, P < 0.01) compared with controls. Dynamic histomorphometry revealed reduced bone formation rate (−45%, P < 0.01) but the number of osteoclasts per bone surface was unaffected in the male Dmp1-ERα −/− mice. The male Dmp1-ERα −/− mice had reduced expression of several osteoblast/osteocyte markers in bone, including Runx2, Sp7, and Dmp1 (P < 0.05). Gonadal intact Dmp1-ERα −/− female mice had no significant reduction in trabecular bone volume but ovariectomized Dmp1-ERα −/− female mice displayed an attenuated trabecular bone response to supraphysiological E2 treatment. Dmp1-ERα −/− mice of both genders had unaffected cortical bone. In conclusion, ERα in osteocytes regulates trabecular bone formation and thereby trabecular bone volume in male mice but it is dispensable for the trabecular bone in female mice and the cortical bone in both genders. We propose that the physiological trabecular bone-sparing effect of estrogen is mediated via ERα in osteocytes in males, but via ERα in osteoclasts in females.

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Female Estrogen Receptor β−/− Mice Are Partially Protected Against Age-Related Trabecular Bone Loss

Cited by 129 publications

References 43 publications

Estrogen actions in the ovary revisited

Estrogen actions in the ovary revisited

Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: comparison with estradiol-17beta

Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice

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