An energetic orphan in an endocrine tissue: A revised perspective of the function of estrogen receptor-related receptor alpha in bone and cartilage

Bonnelye, Edith; Aubin, Jane E.

doi:10.1002/jbmr.1836

Cited by 33 publications

(28 citation statements)

References 99 publications

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“…48,49 The estrogen receptor-related receptors have a demonstrated role in promoting VSMC mineralization and bone formation and hence may be prime candidates for further investigation of these pathways with specific antagonist or silencing studies. 50,51 Interestingly, we found that E2 had site-specific effects on both calcification and ERβ expression. E2 increased plaque calcification and decreased ERβ expression in the aortic sinus but not the innominate artery, in both male and female animals.…”

Section: Discussionmentioning

confidence: 75%

Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation

McRobb

McGrath

Tsatralis

et al. 2017

ATVB

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Objective-Vascular calcification is associated with increased risk of myocardial infarction and stroke. The objective of this work was to examine the ability of 17β-estradiol (E2) to stimulate calcification of vascular smooth muscle cells (VSMC) in vivo, using aged apolipoprotein E-null mice with advanced atherosclerotic lesions, and subsequently to explore underlying mechanisms in vitro. Approach and Results-Silastic E2 capsules were implanted into male and female apolipoprotein E-null mice aged 34 weeks.Plaque and calcified area were measured in the aortic sinus and innominate artery after 8 weeks. Immunohistochemical analysis examined expression of the estrogen receptors (estrogen receptor alpha and estrogen receptor beta [ERβ]). VSMC expression of osteogenic markers was examined using digital polymerase chain reaction. Advanced atherosclerotic lesions were present in all mice at the end of 8 weeks. In both male and female mice, E2 increased calcified area in a site-specific manner in the aortic sinus independently of plaque growth or lipid levels and occurred in association with a site-specific decrease in the proportion of ERβ-positive intimal cells. Calcified lesions expressed collagen I and bone sialoprotein, with decreased matrix Gla protein. In vitro, E2 suppressed ERβ expression and increased VSMC mineralization, demonstrating increased collagen I and II, osteocalcin and bone sialoprotein, and reduced matrix Gla protein and osteopontin. Antagonism or RNA silencing of estrogen receptor alpha, ERβ, or both further increased VSMC mineralization. Conclusions-We have demonstrated that E2 can drive calcification in advanced atherosclerotic lesions by promoting the differentiation of VSMC to osteoblast-like cells, a process which is augmented by inhibition of estrogen receptor alpha or ERβ activity. Visual Overview-An online visual overview is available for this article. studies have demonstrated an inhibitory role for E2 in VSMC calcification in vitro. 26,27 In the context of atherosclerosis, studies support a protective effect of E2 on plaque calcification in women, based on the cardiovascular protective effects of E2 that reduce total plaque burden, attributable to modulation of traditional risk factors, such as plasma high-density lipoprotein and low-density lipoprotein. 28,29 In the clinic, studies show low serum E2 levels associate with increased coronary artery calcification (CAC), [30][31][32] whereas E2 replacement in younger menopausal women reduces CAC. 33,34 These findings are supported by animal studies that show E2 protects against atherosclerotic plaque calcification when associated with beneficial effects on plaque progression. 27,35 However, the mechanistic similarities to bone formation suggest that estradiol could promote vascular calcification in certain circumstances. This dilemma continues to raise the question of how estrogens impact on vascular calcification and plaque progression in the longer term, particularly in the aging vasculature, 36,37 where established, more advanced lesions ...

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Section: Discussionmentioning

confidence: 75%

Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation

McRobb

McGrath

Tsatralis

et al. 2017

ATVB

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“…We and others demonstrated previously that ERR α modulates ROS production in cancer cells [12, 22, 23]. We next examined whether ERR α -mediated MTX resistance was through control of ROS.…”

Section: Resultsmentioning

confidence: 97%

Estrogen-Related Receptor Alpha Confers Methotrexate Resistance via Attenuation of Reactive Oxygen Species Production and P53 Mediated Apoptosis in Osteosarcoma Cells

Chen

Wang

Duan

et al. 2014

BioMed Research International

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Osteosarcoma (OS) is a malignant tumor mainly occurring in children and adolescents. Methotrexate (MTX), a chemotherapy agent, is widely used in treating OS. However, treatment failures are common due to acquired chemoresistance, for which the underlying molecular mechanisms are still unclear. In this study, we report that overexpression of estrogen-related receptor alpha (ERRα), an orphan nuclear receptor, promoted cell survival and blocked MTX-induced cell death in U2OS cells. We showed that MTX induced ROS production in MTX-sensitive U2OS cells while ERRα effectively blocked the ROS production and ROS associated cell apoptosis. Our further studies demonstrated that ERRα suppressed ROS induction of tumor suppressor P53 and its target genes NOXA and XAF1 which are mediators of P53-dependent apoptosis. In conclusion, this study demonstrated that ERRα plays an important role in the development of MTX resistance through blocking MTX-induced ROS production and attenuating the activation of p53 mediated apoptosis signaling pathway, and points to ERRα as a novel target for improving osteosarcoma therapy.

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“…A total of 1,068 genes were induced (>1.5 fold) and 1,445 genes were suppressed (>1.5 fold) in MYC-deficient OCPs compared with control OCPs ( Figure 3A). We used gene set enrichment analysis (GSEA) (25) to broadly test for enrichment of well-defined gene sets from the comprehensive ERRα is not an estrogen receptor, but instead is a nuclear receptor implicated in increasing cellular energy metabolism in tissues such as liver and skeletal muscle in response to environmental challenges that require high energy levels (26)(27)(28). Although ERRα has been implicated in osteoclastogenesis (26,27), a role for ERRα in mediating the effects of MYC on cell phenotype and metabolism has not been previously appreciated, and mechanisms by which ERRα promotes osteoclastogenesis are mostly unknown.…”

Section: Resultsmentioning

confidence: 99%

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

Bae

Lee

Mun

et al. 2017

Journal of Clinical Investigation

101

112

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An energetic orphan in an endocrine tissue: A revised perspective of the function of estrogen receptor-related receptor alpha in bone and cartilage

Cited by 33 publications

References 99 publications

Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation

Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation

Estrogen-Related Receptor Alpha Confers Methotrexate Resistance via Attenuation of Reactive Oxygen Species Production and P53 Mediated Apoptosis in Osteosarcoma Cells

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

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