Absence of ERRα in Female Mice Confers Resistance to Bone Loss Induced by Age or Estrogen-Deficiency

Institut de Génomique Fonctionnelle de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Ecole Normale Supérieure de Lyon, Lyon, France.
PLoS ONE (Impact Factor: 3.23). 11/2009; 4(11):e7942. DOI: 10.1371/journal.pone.0007942
Source: PubMed


ERRalpha is an orphan member of the nuclear hormone receptor superfamily, which acts as a transcription factor and is involved in various metabolic processes. ERRalpha is also highly expressed in ossification zones during mouse development as well as in human bones and cell lines. Previous data have shown that this receptor up-modulates the expression of osteopontin, which acts as an inhibitor of bone mineralization and whose absence results in resistance to ovariectomy-induced bone loss. Altogether this suggests that ERRalpha may negatively regulate bone mass and could impact on bone fragility that occurs in the absence of estrogens.
In this report, we have determined the in vivo effect of ERRalpha on bone, using knock-out mice. Relative to wild type animals, female ERRalphaKO bones do not age and are resistant to bone loss induced by estrogen-withdrawal. Strikingly male ERRalphaKO mice are indistinguishable from their wild type counterparts, both at the unchallenged or gonadectomized state. Using primary cell cultures originating from ERRalphaKO bone marrow, we also show that ERRalpha acts as an inhibitor of osteoblast differentiation.
Down-regulating ERRalpha could thus be beneficial against osteoporosis.

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    • "In this line, we and others have shown that genetic inactivation of the orphan nuclear receptor ERRα in mice leads to resistance to bone loss induced by ovariectomy (used as a model for estrogen-deficiency, thus mimicking menopause) or ageing [23], [24]. Interestingly these phenotypes were not associated with a decrease in osteoclast activity suggesting that ERRα does not modulate bone resorption in vivo at least under the above-mentioned challenging conditions. "
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    ABSTRACT: ERRα is an orphan member of the nuclear receptor family, the complete inactivation of which confers resistance to bone loss induced by ageing and estrogen withdrawal to female mice in correlation with increased bone formation in vivo. Furthermore ERRα negatively regulates the commitment of mesenchymal cells to the osteoblast lineage ex vivo as well as later steps of osteoblast maturation. We searched to determine whether the activities of ERRα on osteoblast maturation are responsible for one or both types of in vivo induced bone loss. To this end we have generated conditional knock out mice in which the receptor is normally present during early osteoblast differentiation but inactivated upon osteoblast maturation. Bone ageing in these animals was similar to that observed for control animals. In contrast conditional ERRαKO mice were completely resistant to bone loss induced by ovariectomy. We conclude that the late (maturation), but not early (commitment), negative effects of ERRα on the osteoblast lineage contribute to the reduced bone mineral density observed upon estrogen deficiency.
    Full-text · Article · Jan 2013 · PLoS ONE
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    • "We have previously shown that ERRa positively regulates osteoblast formation in rat calvarial cells in vitro, acting at multiple developmental times to regulate both proliferation and differentiation events (Bonnelye et al. 2001). However, more recent data with ERRa knockout mice and with human bone marrow stromal cells suggest that ERRa may play a negative regulatory role in other models or at other developmental times (Delhon et al. 2009, Teyssier et al. 2009). Further complicating the issue, one study suggests that an ESRRA gene regulatory variant leading to increased ERRa expression is associated with increased bone mineral density in premenopausal women (Laflamme et al. 2005), although a recent report has failed to confirm the observation (Giroux et al. 2008). "
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    ABSTRACT: The orphan nuclear receptor, estrogen receptor-related receptor α (ERRα) is expressed in osteoblasts and osteoclasts (OCs) and has been proposed to be a modulator of estrogen signaling. To determine the role of ERRα in OC biology, we knocked down ERRα activity by transient transfection of an siRNA directed against ERRα in the RAW264.7 monocyte-macrophage cell line that differentiates into OCs in the presence of receptor activator of nuclear factor κB-ligands and macrophage colony-stimulating factor. In parallel, stable RAW cell lines expressing a dominant-negative form of ERRα and green fluorescent protein (RAW-GFP-ERRαΔAF2) were used. Expression of OC markers was assessed by real-time PCR, and adhesion and transmigration tests were performed. Actin cytoskeletal organization was visualized using confocal microscopy. We found that RAW264.7 cells expressing siRNA directed against ERRα and RAW-GFP-ERRαΔAF2 OCs displayed abnormal spreading, and decreased osteopontin and β3 integrin subunit expression compared with the corresponding control cells. Decreased adhesion and the absence of podosome belts concomitant with abnormal localization of c-src were also observed in RAW-GFP-ERRαΔAF2-derived OCs. In addition, RAW-GFP-ERRαΔAF2-derived OCs failed to transmigrate through osteoblast cell layers. Our data show that the impairment of ERRα function does not alter OC precursor proliferation and differentiation but does alter the adhesion/spreading and migration capacities of mature OCs.
    Full-text · Article · Dec 2010 · Journal of Molecular Endocrinology
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    ABSTRACT: The orphan nuclear receptor estrogen-related receptor-alpha (ERRalpha) has been reported to have both a positive and a negative regulatory role in osteoblastic and adipocytic differentiation. We have studied the role of ERRalpha in osteoblastic and adipogenic differentiation of mesenchymal stem cells. Bone marrow mesenchymal stem cells were isolated from ERRalpha deficient mice and their differentiation capacities were compared to that of the wild-type cells. ERRalpha deficient cultures displayed reduced cellular proliferation, osteoblastic differentiation, and mineralization. In the complementary experiment, overexpression of ERRalpha in MC3T3-E1 cells increased the expression of osteoblastic markers and mineralization. Alterations in the expression of bone sialoprotein (BSP) may at least partially explain the effects on mineralization as BSP expression was reduced in ERRalpha deficient MSCs and enhanced upon ERRalpha overexpression in MC3T3-E1 cells. Furthermore, a luciferase reporter construct driven by the BSP promoter was efficiently transactivated by ERRalpha. Under adipogenic conditions, ERRalpha deficient cultures displayed reduced adipocytic differentiation. Our data thus propose a positive role for ERRalpha in osteoblastic and adipocytic differentiation. The variability in the results yielded in the different studies implies that ERRalpha may play different roles in bone under different physiological conditions.
    No preview · Article · May 2010 · Biochemical and Biophysical Research Communications
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