Trends in Endocrinology & Metabolism
ReviewERR receptors as potential targets in osteoporosis
Section snippets
Bone and osteoporosis
Bone remodeling is a lifelong equilibrium between bone formation by osteoblasts and bone resorption by osteoclasts, which is tightly controlled by various compounds including steroid hormones. The drop in circulating estrogen levels in post-menopausal women results in increased osteoclast activity that is not compensated for by equivalently enhanced osteoblast activity 1, 2. This results in osteoporosis, which is characterized by a progressive reduction in bone mineral density and increased
The ERR receptors
ERR α, β and γ (also known as NR3B1–3; nuclear receptor subfamily 3, group B, members 1–3) are members of a nuclear receptor superfamily, which act as ligand-dependent transcription factors [9]. However, no natural ligand has been identified to date for any of the ERRs, thus they are referred to as orphan receptors [10]. Moreover, crystallographic (at least for ERRα and γ) and cell-based studies have suggested that these receptors act constitutively. Several synthetic compounds have been
ERRs as activators of osteoblast differentiation
A polymorphism in the human ERRα promoter has been identified, which results in variable numbers of ERREs being present, and in turn leading to differential responses to ERRα/PGC-1α-driven positive regulation [27]. A correlation was initially found between this polymorphism and bone mineral density (BMD) in French-Canadian premenopausal women [28], suggesting that elevated ERRα expression was linked to high BMD, although the baseline expression level of the receptor has not been determined in
ERRs as repressors of osteoblast differentiation
The in vivo functions of ERRα in bone were determined through the analysis of the bone parameters of two independently established strains of ERRα knockout (KO) animals with overlapping results 7, 8. In both cases, an increase in trabecular BMD was observed relative to wild-type littermates. Strikingly, one group found that ERRα KO animals were resistant to the bone loss normally observed as a consequence of ageing or ovariectomy [8]. The elevated BMD in unchallenged ERRα KO mice is the result
ERRs: promoters or inhibitors of osteoblast differentiation?
Thus far, we have discussed differing interpretations of the role of ERRα in bone, focusing on whether this receptor activates or represses osteoblast differentiation. There are several tentative explanations for these discrepancies, and there may be others. Studies of in vitro differentiation of rat cells led to the conclusion that ERRα promotes osteoblast differentiation, whereas mouse-based in vivo and in vitro studies resulted in the opposite opinion. These divergent interpretations might
ERRs: treatment targets against osteoporosis?
These recently published results analyzing the roles of ERRs receptors in bone raise the possibility that these receptors might constitute new, estrogen-independent targets, the inhibition of which might be beneficial in the treatment of bone deficiencies, particularly post-menopausal osteoporosis. At least for ERRα, this approach is unlikely to be associated with adverse effects on cancer, because its inhibition reduces breast cancer cell proliferation in vitro and decreases tumorigenesis in
Acknowledgements
Work in our laboratory is funded by Ligue contre le Cancer (comité Rhône), Association pour la Recherche sur le Cancer and Agence Nationale pour la Recherche (grant ANR-08-GENOPATH-012). We thank Christelle Forcet for critical reading of the manuscript.
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Advancing targeted protein degradation for metabolic diseases therapy
2023, Pharmacological ResearchIsolation and functional characterization of a novel endogenous inverse agonist of estrogen related receptors (ERRs)from human pregnancy urine
2019, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :ERRs are known to be critically involved in feto-placental development and in the regulation of estrogen receptor (ER) signaling [3–5]. In addition, ERRs play a pathophysiological role in insulin resistance, heart failure [6] and osteoporosis [7] and Obesity [8] in the human. Furthermore, recent studies suggest that ERRs may represent potential therapeutic targets for several types of cancers [9–13], including breast cancer [14–16].
Estrogen-Related Receptors and the control of bone cell fate
2016, Molecular and Cellular EndocrinologyCitation Excerpt :The receptor has initially been thought to promote osteoblast differentiation when overexpressed in in vitro experiments (Bonnelye et al., 2001). However, analysis of young (8 weeks old) ERRα−/− mice showed that these animals did not display an overt bone phenotype (Delhon et al., 2009; Teyssier et al., 2009; reviewed in Gallet and Vanacker, 2010). Nevertheless, no trabecular bone loss was observed in ERRα−/− mice upon aging (24 weeks) or when females were ovariectomized, in sharp contrast to wild type littermates.
Ligand activation of ERRα by cholesterol mediates statin and bisphosphonate effects
2016, Cell MetabolismCitation Excerpt :ERRα modulates energy metabolism (Giguère, 2008; Luo et al., 2003); ERRα deletion or inhibition confers resistance to obesity and insulin resistance (Luo et al., 2003; Patch et al., 2011; Sladek et al., 1997). ERRα also regulates skeletal remodeling by controlling osteoclastogenesis, a key cellular differentiation process essential for bone resorption (Gallet and Vanacker, 2010; Wan, 2010; Wei et al., 2010); ERRα deletion impairs osteoclast differentiation and bone resorption, leading to increased bone mass (Wei et al., 2010). Furthermore, ERRα is also a critical regulator of multiple cancers (Stein and McDonnell, 2006; Suzuki et al., 2004).
Characterization of a selective inverse agonist for estrogen related receptor α as a potential agent for breast cancer
2016, European Journal of PharmacologyCitation Excerpt :It was found that ERRα, which shares the highest (70%) homologies of their amino acid of DNA-binding domain (DBD) and sequence identity with estrogen receptors (ERs) (Bonnelye and Aubin, 2005), is the closest relatives to ERα and ERβ than any other member of those nuclear hormone receptors. Recent biochemical discoveries also suggest that ERRα exhibits cross-talk with estrogen receptors and it has also share common target genes, such as pS2 (Lu et al., 2001), aromatase (Yang et al., 1998), osteopontin (Gallet and Vanacker, 2010), lactoferrin and other several co-regulatory proteins. Furthermore, ERRα shares high similarity with classical estrogen receptors (ERα and ERβ) at primary sequence, structural levels, and response elements (Zhang and Teng, 2000), but it is classified as an orphan nuclear receptor because it does not bind any natural identified endogenous ligands (Giguere et al., 1988).
Downregulation of ERRα inhibits angiogenesis in human umbilical vein endothelial cells through regulating VEGF production and PI3K/Akt/STAT3 signaling pathway
2015, European Journal of PharmacologyCitation Excerpt :The estrogen related receptor α (ERRα) is a pivotal regulator involved in energy homeostasis and mitochondrial biogenesis by interacting with peroxisome proliferator-activated receptor γ coactivator-1α and 1β (PGC-1α and PGC-1β) (Giguere, 1999; Giguere et al., 2011). ERRα is strongly expressed in various types of cancer and its high expression has also been correlated with poor prognosis in breast, ovarian, colon and other types of tumors (Gallet, Vanacker 2010). Although it has not found an endogenous ligand yet, ERRα can bind to selective synthetic compound XCT790, which was identified as a potent ERRα specific inverse agonist.