Review
ERR receptors as potential targets in osteoporosis

https://doi.org/10.1016/j.tem.2010.06.008Get rights and content

The bone fragility and increased fracture risk associated with osteoporosis in post-menopausal women is a major public health concern. Current treatments for osteoporosis relying on hormone replacement therapies are suspected to have an association with increased breast cancer risk, highlighting the need for identifying new potential targets in bone. Recent data suggest that the estrogen-related receptor (ERR)α, an orphan nuclear receptor, represses osteoblast differentiation, and that its deletion in knockout mouse models results in increased mineral density. Furthermore, modulation of ERRα activity reduces proliferation and tumorigenesis of breast cancer cells. These results indicated that inhibition of ERRα might provide a treatment for osteoporosis without displaying adverse effects in breast cancer. This review focuses on the role of the ERR receptors, and in particular ERRα, in the differentiation of bone precursor cells and its consequences on bone homeostasis, and discusses the possible grounds for the discrepancies reported in the literature.

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.

References (47)

  • F. Syed et al.

    Mechanisms of sex steroid action on bone

    Biochem. Biophys. Res. Comm

    (2004)
  • L.G. Raisz

    Pathogenesis of osteoporosis: concepts, conflicts and prospects

    J. Clin. Invest.

    (2005)
  • C.I. Li

    Relationship between long durations and different regimens of hormone therapy and risk of breast cancer

    JAMA

    (2003)
  • J.A. Collins

    Breast cancer risk with postmenopausal hormonal treatment

    Hum. Reprod. Update

    (2005)
  • K.B. Horwitz

    The year in basic science: update of estrogen plus progestin therapy for menopausal hormone replacement implicating stem cells in the increased breast cancer risk

    Mol. Endocrinol.

    (2008)
  • E. Bonnelye

    The orphan nuclear estrogen receptor-related receptor α (ERRα) is expressed throughout osteoblast differentiation and regulates bone formation in vitro

    J. Cell Biol.

    (2001)
  • I. Delhon

    Absence of estrogen receptor-related-α increases osteoblastic differentiation and cancellous bone mineral density

    Endocrinology

    (2009)
  • C. Teyssier

    Absence of ERRα in female mice confers resistance to bone loss induced by age or estrogen-deficiency

    PLoS ONE

    (2009)
  • A.M. Tremblay et al.

    The NR3B subgroup: an ovERRview

    Nucl. Recept. Signal.

    (2007)
  • B. Horard et al.

    Estrogen receptor-related receptors: orphan receptors desperately seeking ligands

    J. Mol. Endocrinol.

    (2003)
  • G. Deblois

    Genome-wide identification of direct target genes implicates Estrogen-related receptor α as a determinant of breast cancer heterogeneity

    Cancer Res.

    (2009)
  • R.A. Stein

    Estrogen-Related Receptor α is critical for the growth of estrogen receptor negative breast cancer

    Cancer Res.

    (2008)
  • C. Teyssier

    The orphan receptor ERRα interferes with steroid signaling

    Nucleic Acids Res.

    (2008)
  • Cited by (43)

    • Isolation 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 Biology
      Citation 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 Endocrinology
      Citation 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 Metabolism
      Citation 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 Pharmacology
      Citation 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 Pharmacology
      Citation 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.

    View all citing articles on Scopus
    View full text