The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

Börjesson, Anna; Lagerquist, Marie K; Liu, Chen; Shao, Ruijin; Windahl, Sara H; Karlsson, Camilla; Sjögren, Klara; Movérare‐Skrtic, Sofia; Antal, Maria Christina; Krust, Andrée; Mohan, Subburaman; Chambon, Pierre; Sävendahl, Lars; Ohlsson, Claes

doi:10.1002/jbmr.156

Cited by 76 publications

(55 citation statements)

References 44 publications

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“…Patients with estrogen deficiency, caused by a mutation in the aromatase gene, as well as a man with a nonfunctional ERα, causing estrogen resistance, continued to grow after sexual maturation because of unfused growth plates (4,24,37). In addition, we have shown that mice with complete inactivation of ERα (ERα −/− ) have a similar growth plate phenotype as these patients, resulting in a sustained longitudinal bone growth (38,39). High E2 levels in late puberty induce growth plate closure and thereby cessation of growth in humans.…”

Section: Ici Acts As An Inverse Erα Agonist On the Growth Plate Heighmentioning

confidence: 81%

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Movérare‐Skrtic

Börjesson

Farman

et al. 2014

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

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Significance Estrogen exerts important effects in the skeleton, which are primarily mediated via estrogen receptor (ER)α, which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. Previous studies demonstrate that ERα ligands might act as agonists, partial agonists, or antagonists. We demonstrate that the ERα antagonist ICI 182,780 (ICI) acts in a tissue-dependent manner in mice lacking ERαAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. Importantly, ICI exerted a pronounced inverse agonistic activity in the growth plate of mice lacking ERαAF-2. We propose that ERα lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist.

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Section: Ici Acts As An Inverse Erα Agonist On the Growth Plate Heighmentioning

confidence: 81%

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Movérare‐Skrtic

Börjesson

Farman

et al. 2014

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

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“…Western Blot was essentially performed as described previously (37). Further details are provided in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Roles of transactivating functions 1 and 2 of estrogen receptor-α in bone

Börjesson

Windahl

Lagerquist

et al. 2011

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

113

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The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-α (ERα), which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand binding domain. To evaluate the role of ERα AF-1 and ERα AF-2 for the effects of estrogen in bone in vivo, we analyzed mouse models lacking the entire ERα protein (ERα. Estradiol (E2) treatment increased the amount of both trabecular and cortical bone in ovariectomized (OVX) WT mice. Neither the trabecular nor the cortical bone responded to E2 treatment in OVX ERα −/− or OVX ERαAF-2 0 mice. OVX ERαAF-1 0 mice displayed a normal E2 response in cortical bone but no E2 response in trabecular bone. Although E2 treatment increased the uterine and liver weights and reduced the thymus weight in OVX WT mice, no effect was seen on these parameters in OVX ERα −/− or OVX ERαAF-2 0 mice. The effect of E2 in OVX ERαAF-1 0 mice was tissue-dependent, with no or weak E2 response on thymus and uterine weights but a normal response on liver weight. In conclusion, ERα AF-2 is required for the estrogenic effects on all parameters evaluated, whereas the role of ERα AF-1 is tissue-specific, with a crucial role in trabecular bone and uterus but not cortical bone. Selective ER modulators stimulating ERα with minimal activation of ERα AF-1 could retain beneficial actions in cortical bone, constituting 80% of the skeleton, while minimizing effects on reproductive organs.

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“…(Box i) The cortical and (Box ii) the cancellous bone compartments as well as (Box iii) the growth plate of a long bone are depicted in the respective blue boxes. The cells responsible for the particular action along with their dependency or lack thereof on estrogens (E2) in each compartment are deduced from the respective cell-specific ERα deletion murine models of the present work and two earlier papers in which ERα was selectively deleted in osteoclasts (7) and chondrocytes (48). Red arrows point to the site at which the effect summarized in the blue boxes occurs.…”

Section: Figurementioning

confidence: 96%

Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual

Iyer²,

et al. 2012

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The detection of estrogen receptor-α (ERα) in osteoblasts and osteoclasts over 20 years ago suggested that direct effects of estrogens on both of these cell types are responsible for their beneficial effects on the skeleton, but the role of ERα in osteoblast lineage cells has remained elusive. In addition, estrogen activation of ERα in osteoclasts can only account for the protective effect of estrogens on the cancellous, but not the cortical, bone compartment that represents 80% of the entire skeleton. Here, we deleted ERα at different stages of differentiation in murine osteoblast lineage cells. We found that ERα in osteoblast progenitors expressing Osterix1 (Osx1) potentiates Wnt/β-catenin signaling, thereby increasing proliferation and differentiation of periosteal cells. Further, this signaling pathway was required for optimal cortical bone accrual at the periosteum in mice. Notably, this function did not require estrogens. The osteoblast progenitor ERα mediated a protective effect of estrogens against endocortical, but not cancellous, bone resorption. ERα in mature osteoblasts or osteocytes did not influence cancellous or cortical bone mass. Hence, the ERα in both osteoblast progenitors and osteoclasts functions to optimize bone mass but at distinct bone compartments and in response to different cues. IntroductionThe volume of bone mass is determined by the balance between two opposing processes, bone removal (resorption) by osteoclasts and bone formation by osteoblasts. Under physiologic circumstances, formation compensates for the effect of resorption by adding bone either in the same anatomical site from which it was previously resorbed, in a process called remodeling, or in a different site, as in the case of the sculpting of bones during growth, in a process called modeling (1).After birth, long bones in both sexes increase in length. In parallel with linear growth, females and males experience an enlargement and thickening of the bone cortex, because bone apposition at the periosteal (outer) envelope exceeds the widening of the medullar cavity by endocortical resorption. Importantly, with the onset of puberty, estrogens inhibit, while androgens stimulate, periosteal bone formation, thereby contributing to sexual dimorphism and the greater bone mass in the male (2). At the same time, endocortical resorption is attenuated by either estrogens or androgens, producing increased cortical thickness at the end of puberty in both sexes. In line with the inhibitory effect of estrogens on periosteal bone formation, estrogen deficiency in female rodents and postmenopausal women increases periosteal apposition in an attempt to compensate for the endocortical loss of bone. At the end of puberty, estrogens are essential for the closure of the epiphyses and the cessation of linear growth (3).Estrogens also slow the rate of bone remodeling and help to maintain a balance between bone formation and resorption by attenuating the birth rate of osteoclast and osteoblast progenitors in the bone marrow and exerting a proapop...

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The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

Cited by 76 publications

References 44 publications

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Roles of transactivating functions 1 and 2 of estrogen receptor-α in bone

Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual

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