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: A Mediator of Estrogen Response in Bone
Department of Molecular and Medical Genetics, University of Toronto, Toronto M5S 1A8, Canada
Address all correspondence and requests for reprints to: Dr. Jane E. Aubin, Department of Molecular and Medical Genetics, Faculty of Medicine, University of Toronto, Room 6233, Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada. E-mail: jane.aubin{at}utoronto.ca.
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Abstract |
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 Top Abstract IntroductionERR{alpha} Is Expressed in...ERR{alpha} and Bone: A...ERR{alpha}/ERs and the Estrogen...References |
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(ERR) is an orphan nuclear receptor with sequence homology to the estrogen receptors, ER/ß, but it does not bind estrogen. However, several recent studies suggest that ERR not only plays a functional role in osteoblasts but also impinges on the estrogen axis in bone, as it does in at least certain other estrogen target tissues. We summarize here data on ERR and its cellular and molecular modes of action that have broad implications for considering the potential role of this orphan receptor as a new therapeutic target in osteopenic disorders such as osteoporosis as well as other estrogen-responsive conditions. |
Introduction |
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TopAbstractIntroductionERR{alpha} Is Expressed in...ERR{alpha} and Bone: A...ERR{alpha}/ERs and the Estrogen...References |
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and ERß [NR3A1 and NR3A2, respectively, according to the Nuclear Receptors Nomenclature Committee (1)], which belong to the superfamily of nuclear receptors (2, 3). The nuclear receptors are transcription factors comprising both ligand-dependent molecules (e.g. steroid hormone, thyroid hormone, retinoic acid, and vitamin D receptors) and a large number of so-called orphan receptors for which ligands have not been identified (4, 5).
The first orphan nuclear receptors identified were proteins related to ER and were referred to as ER-related receptors (ERRs) (6). ERR and ERRß (NR3B1 and NR3B2) were identified by low-stringency screening of cDNA libraries with a probe encompassing the DNA binding domain of human ER. A third ERR, ERR
, was identified by yeast two-hybrid screening with the glucocorticoid receptor-interacting protein 1 as bait (7). The DNA-binding domain of ERRs and ERs is highly conserved; however, other parts of the proteins share very little homology (6, 7). Thus, sequence alignment of ERR and the ERs reveals a high similarity (68%) in the DNA-binding domain and a moderate similarity (36%) in the ligand-binding E domain, which may explain the fact that ERR does not bind estrogen. Nevertheless, considerable data support the idea that ERR may impinge on the estrogen pathway. ERR interacts with ERs through protein-protein interactions in vitro and recognizes the same DNA binding element as ERs (8, 9). ERR, ERRß, and ER can bind to and activate transcription through both the functional estrogen response element (ERE), and the steroid factor 1 response element (SFRE) (Fig. 1
). ERß DNA-binding and transcriptional activity, on the other hand, is restricted to the ERE. ERR and thyroid hormone receptors (TRs) can also both bind to and activate transcription through the thyroid hormone response element (TRE) (10) (Fig. 1). ERR has been shown recently to activate transcription via an activator protein 1 (AP-1) site that is also a DNA binding site used by ERs (11). Several coactivators are known to interact with ERRs and ERs, including steroid receptor coactivator 1, peroxisome proliferator-activated receptor- coactivator-1 (PGC-1), activator of thyroid and retinoic acid receptor, and glucocorticoid receptor-interacting protein 1 (10, 12). It has been shown that not only ERR (13, 14) but also ER (15) binds to and activates transcription of the ERR promoter. These data suggest possible biological overlap between ERRs and ERs via their DNA binding (ERE, SFRE, and AP-1) and transcriptional regulatory activity.
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is expressed in tissues in which estradiol is known to play an essential role, e.g. the female and male reproductive organs, mature ovocytes in the ovary, and spermatocytes in the testis. It is also expressed in nonreproductive tissues such as mammary glands, heart, and nervous system in which estrogen has important physiological functions (16, 17, 18). In addition, estradiol has been linked to numerous diseases including breast cancer in which ERR is highly expressed and regulates the expression of pS2, a human breast cancer prognostic marker (19), strengthening the hypothesis of ER-ERR-estrogen (E2) cross-talk. Another important estrogen-dependent disease is postmenopausal osteoporosis, a bone pathology in which we have implicated ERR.
Bone is a highly metabolically active tissue in which the processes of osteoblastic bone formation and osteoclastic resorption are continuous throughout life. Steroid hormones (e.g. E2, progesterone, androgen) play an important role in bone cell development and maintenance of normal bone architecture (20, 21). A clinically significant manifestation of the loss of E2 production by the ovary at menopause is the increased bone turnover and accelerated loss of bone mass that leads to increased bone fragility and fracture risk, commonly called osteoporosis (22, 23). A positive effect of estrogens on bone homeostasis has been documented in postmenopausal osteoporosis in which bone loss can be stopped by administration of natural or synthetic estrogens (24). Although the bone-preserving effect of E2 replacement is indisputable, the molecular and cellular mechanism(s) mediating this effect remain unclear. Indeed, the targeted deletion of one or both ERs fails to recapitulate the severe increase in bone turnover observed after suppression of E2 after menopause or gonadectomy in female mice (25). Given the homology of ERR to the ERs and the evidence that it may interact with ER and modify E2 effects on at least some genes, we hypothesized that ERR may intervene in E2 signaling in bone.
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ERR Is Expressed in Bone Cells
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TopAbstractIntroductionERR{alpha} Is Expressed in...ERR{alpha} and Bone: A...ERR{alpha}/ERs and the Estrogen...References |
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in the skeleton is only beginning to be investigated. Among the earliest evidence that ERR might be functionally important in bone was the spatial and temporal correlation seen between high ERR mRNA expression and the formation of ossification zones during mouse development. ERR mRNA was detected very early at sites of endochondral ossification [embryonic day (E)15.5 in ribs and vertebrae; E17.5 in forelimb bones] (18, 26). ERR mRNA was also found to be highly expressed in several human and mouse osteoblastic cell lines (TE85, SaOS, MC3T3) and normal human bone (26). When osteoblast development was studied in vitro in the rat calvaria (RC) cell bone nodule culture model, ERR mRNA was highly expressed throughout the proliferation-differentiation sequence, i.e. in colonies comprising primitive proliferative progenitors expressing only osteopontin (OPN) through colonies containing mature postproliferative osteoblasts expressing the late marker osteocalcin (OCN) and mineralizing deposited osteoid (27).
That not only ERR mRNA but also protein is highly expressed in all developing and adult endochondral and intramembranous bones analyzed was confirmed by immunocytochemistry, which revealed high ERR staining in not only cranial sutural cells but also periosteal cells, osteoblasts, lining cells, and osteocytes (27, 28). ERR antibodies also label tartrate-resistant acid phosphatase-positive cells in the rat femur after ovariectomy (OVX) and the mouse monocyte RAW 264.7 cell line, which differentiates into osteoclast-like cells in the presence of receptor activator of nuclear factor 
B ligand (29). These data suggest a potential function of ERR in osteoblasts and osteoclasts and therefore in bone formation, resorption, and turnover.
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ERR and Bone: A Physiological Function and Target Genes
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TopAbstractIntroductionERR{alpha} Is Expressed in...ERR{alpha} and Bone: A...ERR{alpha}/ERs and the Estrogen...References |
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in osteoprogenitors and proliferating primary RC cell cultures correlates with its detection from the onset of osteogenesis in vivo and reinforces the hypothesis that ERR may play a role in bone formation from early stages. Blocking ERR by treatment with antisense oligonucleotides in RC cells during the proliferation phase of cultures decreases cell number, an inhibition that decreases bone nodule formation at later stages (27). Consistent with this, the cell cycle regulator cyclin D1 was inhibited as was runt-related transcription factor (Runx) 2 (30), an early marker of osteoblast development and a transcription factor known as a bone master gene, and the noncollagenous bone protein bone sialoprotein (BSP), which is expressed in a biphasic manner in both relatively immature precursors and again in more mature osteoblasts associated with mineralizing matrix (31, 32, 33). Independently of an effect on proliferation, inhibition of ERR during osteoblast differentiation also has a large impact on bone nodule formation. Although alkaline phosphatase-positive colonies form in RC cell cultures after treatment with ERR antisense oligonucleotide treatment, these are very flat, unmineralized, and easily distinguishable from the typical three-dimensional mineralized bone nodules that form in control (untreated or treated with sense or scrambled oligonucleotides) cultures. Concomitantly, Runx2, BSP, and OCN were also inhibited. Not only loss of function but also gain of function of ERR affects bone formation, with transient overexpression of ERR in RC cells increasing osteoblast differentiation and bone formation (27).
Together these data support a role for ERR in bone formation at both proliferation and differentiation stages. The fact that three genes known to be involved in bone formation (Runx2, BSP, and OCN) are dysregulated in cultures in which ERR levels are altered supports this hypothesis and raises the possibility that one or all of these genes are ERR target genes, a possibility that remains to be tested. However, other osteoblast-associated genes are already known to be directly regulated by ERR (Table 1). One of these is OPN, a noncollagenous bone matrix protein expressed by osteoblasts and osteoclasts (34) and the first identified ERR target gene known to have a function in bone formation and resorption (35, 36, 37). The mouse OPN promoter contains two discrete SFREs through which ERR binds and transactivates in vitro (35). ERR and OPN mRNAs are expressed in spatially and temporally similar windows at the onset of osteogenesis at E15.5 (ERR) and E16 (OPN) during mouse development (17, 38) and throughout osteoblast development in vitro (27). Interestingly, we found a differentiation stage-specific regulation of OPN in osteoblast lineage cells; although the underlying mechanism is not yet clear, differentiation stage-specific expression of coactivators or repressors including ERR binding partners is one interesting hypothesis.
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target gene known to have a function in bone belongs also to the nuclear receptor family. ERR directly up-regulates expression of c-erbA1, the gene coding for the TR isoform TR, in human and rat fibroblasts via its binding and transactivation on a perfect and unique SFRE site in the human c-erbA1 promoter (16). Notably, T3 has been shown to elicit both anabolic and catabolic effects on the skeleton and has effects on proliferation and differentiation of both osteoblasts and osteoclasts (reviewed in Ref. 39). Deletion of TR1/2 in mice causes growth retardation and impaired development of epiphyseal bone (40, 41), a role that may be shared by ERR as an upstream regulator of TR.
Aromatase, which converts androgens to estrogens, is a known target gene of ERR, at least in breast and HepG2 cells in which ERR binds to a CCAAGGTCAGAAAT sequence and activates transcription (42, 43). Aromatase contributes to extragonadal estrogen biosynthesis and is known to be an important regulator of bone cell function. Patients with aromatase deficiency suffer from severe osteoporosis with increased bone turnover (44, 45, 46). Deletion of the aromatase gene in mouse induces osteopenia characterized by significant decreases in trabecular bone volume and thickness (47, 48). More generally, aromatase activity is detectable in many tissues including the brain, liver, prostate, placenta, skin fibroblasts, adipose tissue, and osteoblasts (49). It will be important to determine whether ERR regulates expression of aromatase in osteoblasts and contributes to estrogen biosynthesis locally (paracrine or intracrine fashion) in bone, an action that would impose activity of the orphan receptor on ER/ERß skeletal function.
ERR up-regulates endothelial nitric oxide synthase (eNOS) mRNA and protein expression in bovine pulmonary artery endothelial cells via a DNA site, not yet defined, between –1001/–743 and –743 /–265 in the eNOS promoter (50). It was postulated that the regulation of the eNOS promoter is through AP-1 sites, a regulatory mechanism used by estrogen on the cyclin D1 promoter (51). ERR was also found to activate transcription at AP-1 sites in the presence but not absence of 4-hydroxytamoxifen, which suggests that the ERRs may modulate expression of their target genes in a manner not unlike ERs (11). eNOS is the predominant nitric oxide synthase enzyme expressed in bone by osteoblasts, osteoclasts, and osteocytes (52), suggesting coexpression of ERR and eNOS in all these bone cells. Exposure to nitric oxide (NO) in vitro (cultured osteoclasts) and nitric oxide synthase inhibitor in vivo inhibits bone resorption and reduces bone mass, respectively, suggesting an endogenous inhibitory function on osteoclast activity consistent with the inhibitory effect of NO donors on osteoclastic bone resorption (53). Transient low-level production of NO by eNOS is associated with stimulation of osteoblast activity and bone formation. eNOS knockout mice display growth defects in tibiae and femur, with higher turnover and reduced bone formation and volume, resulting from reduced number, synthetic and mineralizing activity of osteoblasts in vivo, and retarded proliferation and differentiation in vitro (54). These data demonstrate that distinct components of the osteoblast phase of the bone remodeling cycle are altered in eNOS knockout mice, implicating NO-dependent signaling via eNOS in the regulation of osteoblast growth and differentiation. Although eNOS regulation by ERR has not yet been shown in bone cells, it is a potential pathway by which ERR may regulate osteoblast proliferation/differentiation.
Finally, lactoferrin, another known ERR target gene in at least certain cell types (12, 55), has been reported to be a potent regulator of bone cell activity. This iron-binding glycoprotein increases proliferation and differentiation in human and rat osteoblast-like cells, inhibits osteoclastogenesis in vitro, and is potently anabolic in vivo as judged by administration over the calvaria in adult mice (56).
Based on these data and the growing list of potential ERR target genes in bone (Table 1
), ERR is an important potential regulator of bone biology. Thus, the phenotype of ERR knockout mice may be surprising, given that they display no reported bone anomalies but do have reduced body weight and reduced peripheral fat deposits associated with dysregulation of several genes involved in adipogenesis and energy metabolism (57). Whether the lack of a bone phenotype is due to functional redundancy of ERR family members is not yet known but would not be surprising by analogy with what is seen with other nuclear receptor families. It therefore remains of interest to assess developmental and adult phenotypes in mice with genetically altered ERRs with or without concomitant alterations in, e.g. ERs.
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ERR/ERs and the Estrogen Axis in Bone
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TopAbstractIntroductionERR{alpha} Is Expressed in...ERR{alpha} and Bone: A...ERR{alpha}/ERs and the Estrogen...References |
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does not bind E2 as a ligand, but a significant amount of data suggests that ERR expression is regulated by E2 in vivo and in vitro and that its transcriptional activity is modulated by estrogenic and antiestrogenic compounds.
ERR expression is increased by estrogen in a differentiation stage-specific manner in RC cells in vitro and decreased in vivo after OVX of rats, a well-established model of postmenopausal osteoporosis (29) (Fig. 2, I). The ERR gene is also stimulated by E2 in tissues other than bone, in particular in estradiol-sensitive organs. Liu and colleagues (15) demonstrated that the expression of the ERR gene is stimulated by estrogen in mouse uterus and heart but not in liver. They also established the estrogen responsiveness of the endogenous ERR gene in human uterine and mammary gland cell lines, suggesting that E2 regulation of ERR is tissue and cell type dependent (15, 58). Chromatin immunoprecipitation assays done with the MCF-7 mammary gland cell line revealed interaction between ER and a DNA element containing multiple steroid hormone response element half-sites (MHREs) that is found in the human and mouse ERR promoters (14, 15) (Fig. 2, II). E2 treatment enhanced the association of ER and the MHREs, suggesting that the ERR gene is a downstream target of ER and providing one mechanism by which ERR modulates E2 response. The fact that up-regulation of ERR after E2 treatment in RC cells is blocked by addition of the E2 antagonist ICI 182,780 suggests that ERR expression is also mediated through ERs in this osteoblast cell model (29).
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in osteoblasts in vivo and in vitro (28). mRNAs for both ERs are expressed in intramembranous bone (calvaria) and primary RC cells and endochondral bone (tibia) and primary bone marrow stroma cells, but ERR mRNA is more abundantly and widely expressed than either of the two ERs (28). The expression patterns of ERR, ER, and ERß in the developing RC suggest that all three receptors may be required for the formation of bone but at different times and for different functions. Indeed, ERR is expressed at all stages of osteoblast differentiation (osteoprogenitors, osteoblasts, lining cells, and osteocytes) in vivo and in vitro, whereas ERß is expressed in sutural cells (osteoprogenitors) and ER is expressed in more mature osteoblasts, suggesting that the receptors may function in different pairs in different groups of osteoblasts.
Whether ERR and ERs regulate the expression of the same target genes in those cells in which they are coexpressed, i.e. via protein-protein interactions (8), is not yet known (Fig. 2, III). However, the regulation of ERR expression by E2 in RC cells and femurs from ovariectomized rats, the capacity of ER to bind and activate the ERR promoter, and the capacity of ERR and ER to bind the same DNA target sequences (the SFRE and ERE) on the OPN promoter support this idea (9) (Fig. 2, IV). Binding of ERß to the ERR promoter and interactions between ERR and ERß have not yet been described, although ER and ERß have been reported to recognize the same ERE (9). However, the complexity of the functional relationships between ERR and ER is probably not limited to protein-protein interactions or the transcriptional regulation of ERR by ER. It is known that not only receptor coexpression but also expression levels, receptor-DNA binding affinities, and the nature of the response elements all influence transcriptional regulation by nuclear receptors. Moreover, the availability of coactivators or corepressors and the presence of ligands also play an important role in regulating target gene expression (59, 60). ER isoform expression patterns and the stage of differentiation have also been shown to influence the response of human osteoblastic cells to estrogens (61) and mice lacking a functional ER vs. a functional ERß have different bone abnormalities (25). All of this supports the hypothesis that ERR, together with ERs, may function in different pairs in different groups of osteoblasts to manifest nonredundant/nonidentical functions in different cellular contexts.
Consistent with what has been reported for ERs (62, 63, 64), ER, ERß, and ERR are coexpressed in adult bone in osteoblasts and osteocytes in which they may interact in one or more pathways to control maintenance and turnover of bone. The fact that ERR levels are regulated in bone when E2 levels are altered, together with the capacity of changes in ERR levels to modify bone formation in vitro, makes ERR an interesting new molecular target for E2 and hormone replacement therapies for bone diseases such as osteoporosis. As already noted, several putative ERR target genes (aromatase, OPN, and eNOS) have a link with estrogen. Aromatase is the enzyme converting androgens to estrogens, OPN appears to be required in OVX-induced bone resorption (65), and the stimulatory effect of estrogen on osteoblast proliferation and differentiation requires local production of NO by bone cells via eNOS (54, 66) (Fig. 2, V). How ERR impinges on these estrogen responses in bone is the subject of ongoing studies, and, in this regard, transgenic mice overexpressing ERR specifically in bone (67) (Zirngibl, R. A., and J. E. Aubin, unpublished observations) may be useful tools.
Although ERRs share high amino acid sequence homology with ERs, E2 is not a ligand of ERRs. Structure-function studies showed that ERRs have ligand-binding pockets smaller than those in ERs, and these and other studies (10, 68, 69, 70, 71) provided evidence that ERRs may activate gene transcription constitutively. However, during the last several years, antagonists of ERRs have been identified. Two organochlorine pesticides with E2-like activity, toxaphene and chlordane, suppress the constitutive activity of ERR (72). The synthetic estrogen diethylstilbestrol and the antiestrogen 4-hydroxytamoxifen were also found to be antagonists of ERRs (73, 74). Two inverse agonists, thiadiazolopyrimidinone 1a and a derivative XCT790, which interfere with PGC-1/ERR-dependent signaling, have also been reported (75, 76). Clearly identification of a physiological ligand(s) is of great interest. Suetsugi et al. (77) found that flavone (6,3',4'-trihydroxyflavone) and isoflavone (genistein, daidzein, and biochanin A) phytoestrogens can act as agonists of ERRs. Interestingly, genistein enhances osteogenesis and represses adipogenic differentiation in human primary bone marrow stromal cell cultures (78), an effect consistent with our data on ERR effects in RC cell cultures. Like ERR in RC cells (29), genistein increased alkaline phosphatase expression and the osteoprotegerin to receptor activator of nuclear factor B ligand ratio and decreased peroxisomal proliferator-activated receptor- and lipoprotein lipase expression (78). Although Heim et al. (78) suggest that the effects of genistein are mediated by ERs, it is notable that the binding of flavone and isoflavone ligands to ERR increased its transcriptional activity to the levels of those of ER and ERß in the presence of the same compounds at similar concentrations (77). These observations have important implications for interpreting and dissecting the relative roles of ERs vs. ERR in bone but suggest that agonist action on ERR may help to prevent bone loss in women who take phytoestrogens.
In conclusion, growing evidence suggests that ERR may be involved in bone formation, maintenance and turnover in a complex pathway(s) in which ERR may act with or without ERs in different cohorts of cells to regulate expression of target genes. The observations also suggest that appropriate use of agonists and antagonists of ERR may provide a novel therapeutic approach for osteopenic disorders such as osteoporosis. It must be acknowledged, however, that activation of ERR as a therapeutic tool for osteoporosis may have deleterious effects in other organs. As described earlier, ERR is highly expressed in human breast cancer and is, in fact, considered an unfavorable biomarker for that disease (79). Our observation that ERR regulates osteoprogenitor proliferation by regulating at least one cell cycle gene, cyclin D1, a key feature also of the mitogenic response to estrogen, suggests that activation of ERR may be beneficial for bone but counterindicated in breast. Therefore, strategies similar to those directing selective estrogen receptor modulator therapy, i.e. identification of ERR agonists with target organ specificity, may be required and will be a considerable challenge for the future.
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Footnotes |
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Present address for E.B.: Laboratoire de Biologie Moleculaire et Cellulaire, Ecole Normale Superieure de Lyon, Lyon, France.
First Published Online February 15, 2005
Abbreviations: AP-1, Activator protein 1; BSP, bone sialoprotein; E, embryonic day; E2, estrogen; ER, estrogen receptor; eNOS, endothelial nitric oxide synthetase; ERE, estrogen response element; ERR, estrogen receptor-related receptor; MHRE, multiple steroid hormone response element half-site; NO, nitric oxide; OCN, osteocalcin; OPG, osteoprotegerin, OPN, osteopontin; OVX, ovariectomy; PGC-1, peroxisome proliferator-activated receptor- coactivator-1; RC, rat calvaria; Runx, runt-related transcription factor; SFRE, steroid factor 1 response element; TR, thyroid hormone receptor; TRE, thyroid hormone response element.
Received November 3, 2004.
Accepted January 31, 2005.
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TopAbstractIntroductionERR{alpha} Is Expressed in...ERR{alpha} and Bone: A...ERR{alpha}/ERs and the Estrogen...References |
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1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements. Mol Endocrinol 11:342–352, but not by ERß. EMBO J 18:4270–4279[CrossRef][Medline]
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is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol 17:5400–5409[Abstract]
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coactivator 1 (PGC-1) signaling by an estrogen-related receptor (ERR) ligand. Proc Natl Acad Sci USA 101:8912–8917 and estrogen-related receptor associate with unfavorable and favorable biomarkers, respectively, in human breast cancer. Cancer Res 62:6510–6518This article has been cited by other articles:
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