Molecular and cellular mechanisms of estrogen action on the skeleton

Rickard, David J.; Subramaniam, Malayannan; Spelsberg, Thomas C.

doi:10.1002/(sici)1097-4644(1999)75:32+<123::aid-jcb15>3.0.co;2-k

Cited by 69 publications

(53 citation statements)

References 42 publications

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“…It has been established that in the presence of CSF-1 sufficient to maintain cell growth and survival, RANKL, via its tumor necrosis factor family receptor RANK, is sufficient to induce complete osteoclastic differentiation from hematopoietic precursors and that knock-out mice with defects in the RANKL system cannot form osteoclasts (26). It is also established that estrogen withdrawal causes rapid skeletal degradation, an effect that certainly involves other cells, including osteoblasts, but that has also been hypothesized to involve direct effects on osteoclast formation (3)(4)(5). This report demonstrates that phytoestrogens and ␤-estradiol directly reduce osteoclastic differentiation in the murine RAW264.7 cell model.…”

Section: Discussionmentioning

confidence: 99%

“…The effects of estrogens on skeletal cells are complex, and the mechanism(s) of action are controversial (reviewed in Ref. 3). However, transgenic and knock-out mice with varying ER␣ and ER␤ expression established that estrogen effects on bone involve ER␣ and ER␤, which modulate signaling pathways involving Erk and nitric oxide and perform direct transcriptional activity (4).…”

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confidence: 99%

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Negative Regulation of RANKL-induced Osteoclastic Differentiation in RAW264.7 Cells by Estrogen and Phytoestrogens

Palacios

Robinson

Borysenko

et al. 2005

Journal of Biological Chemistry

108

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We studied estrogen effects on osteoclastic differentiation using RAW264.7, a murine monocytic cell line. Differentiation, in response to RANKL and colony-stimulating factor 1, was evaluated while varying estrogen receptor (ER) stimulation by estradiol or nonsteroidal ER agonists was performed. The RAW264.7 cells were found to express ER␣ but not ER␤. In contrast to RANKL, which decreased ER␣ expression and induced osteoclast differentiation, 10 nM estradiol, 3 M genistein, or 3 M daidzein all increased ER␣ expression, stimulated cell proliferation, and decreased multinucleation, with the effects of estrogen > daidzein > genistein. However, no estrogen agonist reduced RANKL stimulation of osteoclast differentiation markers or its down-regulation of ER␣ expression by more than ϳ50%. Genistein is also an Src kinase antagonist in vitro, but it did not decrease Src phosphorylation in RAW264.7 cells relative to other estrogen agonists. However, both phytoestrogens and estrogen inhibited RANKL-induced IB degradation and NF-B nuclear localization with the same relative potency as seen in proliferation and differentiation assays. This study demonstrates, for the first time, the direct effects of estrogen on osteoclast precursor differentiation and shows that, in addition to effecting osteoblasts, estrogen may protect bone by reducing osteoclast production. Genistein, which activates ERs selectively, inhibited osteoclastogenesis less effectively than the nonselective phytoestrogen daidzein, which effectively reproduced effects of estrogen.Estrogen is a key regulator of skeletal mass. Most estrogen effects are mediated by estrogen receptors (ERs) 1 ␣ and ␤, which are ligand-dependent transcriptional regulators. ER␣, the classical sex-related receptor, has a wide tissue distribution and is found in osteoclasts and osteoclast precursors as well as osteoblasts; ER␤ is primarily found in epithelial and mesenchymal tissues, including the mesenchymal stem cell-derived bone-forming cells, osteoblasts. There are also estrogen-binding proteins that are not transcription factors, and some estrogenic effects are mediated by membrane receptors linked to calcium (1, 2). The effects of estrogens on skeletal cells are complex, and the mechanism(s) of action are controversial (reviewed in Ref.3). However, transgenic and knock-out mice with varying ER␣ and ER␤ expression established that estrogen effects on bone involve ER␣ and ER␤, which modulate signaling pathways involving Erk and nitric oxide and perform direct transcriptional activity (4). Estrogen responses in mesenchymal stem cell-derived bone-forming cells, osteoblasts, are extensively studied. The effects of estrogens on osteoblasts include regulation of synthesis of the osteoclast differentiation factor RANKL relative to its inhibitor osteoprotegerin (5, 6), which may secondarily regulate osteoclast formation and activity.In contrast, primary estrogen effects on osteoclast differentiation and function are largely uncharacterized. ER␣ is present in osteoclasts (7), whereas ER␤ is...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Negative Regulation of RANKL-induced Osteoclastic Differentiation in RAW264.7 Cells by Estrogen and Phytoestrogens

Palacios

Robinson

Borysenko

et al. 2005

Journal of Biological Chemistry

108

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“…The importance of estrogen and nuclear ERs to skeletal growth and bone metabolism is supported by a body of evidence (Eriksen et al 1988, Bodine et al 1998, Rickard et al 1999, Compston 2001. Nevertheless, the network of interactions and molecular mechanisms is very complex and the design of a unique model of estrogen action in bone is very difficult.…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, the network of interactions and molecular mechanisms is very complex and the design of a unique model of estrogen action in bone is very difficult. Recent advances have defined potential sites of estrogen action within the bone microenvironment: these mainly include proliferation and differentiation of osteoprogenitor cells, activity of mature osteoblasts and osteoclasts, bone matrix synthesis and bone resorption, and interaction with co-regulatory factors (Rickard et al 1999.…”

Section: Introductionmentioning

confidence: 99%

Modulation of gene expression in human osteoblasts by targeting a distal promoter region of human estrogen receptor-alpha gene

Lambertini

Penolazzi²,

Sollazzo³

et al. 2002

Journal of Endocrinology

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Estrogen receptor (ER) is expressed during osteoblast differentiation; however, both its functional role in bone metabolism and its involvement in osteoporotic pathogenesis caused by estrogen deficiency are not well understood. Loss of ER gene expression could be one of the mechanisms leading to osteoporosis. Therefore, we investigated a possible modulation of ER gene expression in a human osteoblastic cell line and in four primary osteoblast cultures by using a decoy strategy. Double stranded DNA molecules, mimicking a regulatory region of the ER gene promoter (DNA-102) and acting as a 'silencer' in breast cancer cells, were introduced into osteoblasts as 'decoy' cis-elements to bind and functionally inactivate a putative negative transcription factor, and thus to induce ER gene expression.We found that the DNA-102 molecule was able to specifically bind osteoblast nuclear proteins.Before decoy treatment, absence or variable low levels of ER RNAs in the different cultures were detected. When the cells were transfected with the DNA-102 decoy, an increase in expression of ER and osteoblastic markers, such as osteopontin, was observed, indicating a more differentiated osteoblastic phenotype both in the cell line and in primary cultures. These results showed that the DNA-102 sequence competes with endogenous specific negative transcription factors that may be critical for a decrease in or lack of ER gene transcription. Therefore, osteoblastic transfection with the DNA-102 decoy molecule may be considered a tempting model in a putative therapeutic approach for those pathologies, such as osteoporosis, in which the decrease or loss of ER expression plays a critical role in bone function.

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“…Estrogen has major effects on OB and osteoclast (OC) differentiation, including OB proliferation, differentiation, matrix production, and mineralization [Hughes et al, 1996;Robinson and Spelsberg, 1997;Oursler, 1998;Khosla et al, 1999;Rickard et al, 1999Rickard et al, , 2002aSpelsberg et al, 1999]. Decreased E 2 levels are known to be one of the main causes of osteoporosis [Melton, 1995;Gallagher, 1996] and there is abundant evidence demonstrating a critical role for E 2 in regulating bone metabolism and homeostasis in both [Riggs et al, 2002].…”

Section: Estrogen Action In Ob Cellsmentioning

confidence: 99%

Estrogen‐TGFβ cross‐talk in bone and other cell types: Role of TIEG, Runx2, and other transcription factors

Hawse

Subramaniam

Ingle

et al. 2007

J of Cellular Biochemistry

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It is well established that E 2 and TGFβ have major biological effects in multiple tissues, including bone. The signaling pathways through which these two factors elicit their effects are well documented. However, the interaction between these two pathways and the potential consequences of cross-talk between E 2 and TGFβ continue to be elucidated. In this prospectus, we present known and potential roles of TIEG, Runx2, and other transcription factors as important mediators of signaling between these two pathways. KeywordsBone; Runx2; TIEG; Estrogen; TGFβ; osteoblast; osteoclast Estrogen (E 2 ) and TGFβ are known to be major regulators of skeletal formation and maintenance Spelsberg et al., 1999;Rickard et al., 2002a;Janssens et al., 2005]. In the past there have been numerous reports about the interaction (cross-talk) between these two important regulators, many of which involve transcription factors. This prospectus summarizes some of these studies and proposes some potential areas of crosstalk in osteoblast (OB) cells which includes Runx2 and another important factor discovered by our laboratory, the TGFβ inducible early gene-1 (TIEG), also known as Krüppel-like transcription factor-10 (KLF-10) [Subramaniam et al., 1995]. ESTROGEN ACTION IN OB CELLSThe skeleton is one of the main targets of E 2 action in the body as it regulates bone growth and remodeling. Estrogen has major effects on OB and osteoclast (OC) differentiation, including OB proliferation, differentiation, matrix production, and mineralization [Hughes et al., 1996;Robinson and Spelsberg, 1997;Oursler, 1998;Khosla et al., 1999;Rickard et al., 1999Rickard et al., , 2002aSpelsberg et al., 1999]. Decreased E 2 levels are known to be one of the main causes of osteoporosis [Melton, 1995;Gallagher, 1996] and there is abundant evidence demonstrating a critical role for E 2 in regulating bone metabolism and homeostasis in both [Riggs et al., 2002]. It is important to understand E 2 action in the skeleton to better define the mechanisms of bone loss and in order to develop new approaches to prevent and treat osteoporosis. The primary mechanism by which E 2 elicits its effects on target tissues is by binding to, and activating, the two major estrogen receptor (ER) isoforms, ERα and ERβ. It was originally believed that ERβ only modulated the activity of ERα; however, recent studies by our laboratory and others have demonstrated that these two receptors regulate distinct sets of genes in OBs [Waters et al., 2001;Rickard et al., 2002b;Monroe et al., 2003a;Kian Tee et al., 2004;Stossi et al., 2004;Monroe et al., 2005]. Adding to this complexity is the identification of a host of nuclear receptor co-activators and corepressors that modulate E 2 action [McKenna et al., 1999]. OBs express both ERα and ERβ, and both are differentially expressed during OB maturation. The ERα concentrations in rat OB cells increase by almost 10-fold during the differentiation of OB precursor cells into mature OBs, whereas ERβ concentrations increase only slightly, but remain ...

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Molecular and cellular mechanisms of estrogen action on the skeleton

Cited by 69 publications

References 42 publications

Negative Regulation of RANKL-induced Osteoclastic Differentiation in RAW264.7 Cells by Estrogen and Phytoestrogens

Negative Regulation of RANKL-induced Osteoclastic Differentiation in RAW264.7 Cells by Estrogen and Phytoestrogens

Modulation of gene expression in human osteoblasts by targeting a distal promoter region of human estrogen receptor-alpha gene

Estrogen‐TGFβ cross‐talk in bone and other cell types: Role of TIEG, Runx2, and other transcription factors

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