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    ASBMR 2011 Annual Meeting

    Estrogen Receptor-Related Receptor Gamma (ERRĪ³) Is a Regulator of Bone Turnover

    Category: Steroid Hormones and Receptors

    Poster Sessions, Presentation Number: SA0484
    Session: Poster Session I & Poster Tours*
    Saturday, September 17, 2011 11:00 AM - 1:00 PM, San Diego Convention Center, Hall GH

    * Marco Cardelli, University of Toronto, CANADA, Ruolin Guo, University of Rochester, USA, Jonathan Boetto, University of Toronto, Canada, Ralph Zirngibl, University of Toronto, CANADA, Jane Aubin, University of Toronto Faculty of Medicine, CANADA

    Sex steroids, such as estrogen, play a role in the onset and severity of symptoms in arthritis and osteoporosis. Estrogen exerts its activity via its receptors, estrogen receptor α and β, which are members of the nuclear receptor family. There are also members of the family for which ligands have not been identified, the so-called orphan receptors. Amongst these are the estrogen receptor-related receptors (ERRs), ERRα, ERRβ, and ERRγ. Previously, we showed that ERRα is highly expressed in bone and cartilage and that it plays a functional role in osteogenesis and chondrogenesis in vitro (Bonnelye et al., 2001; Bonnelye et al., 2007). We have also found that ERRγ is expressed in skeletal cells and tissues, albeit at levels significantly lower than ERRα. Consistent with recent evidence from in vitro and ectopic bone formation experiments, suggesting that ERRγ is a negative regulator of osteogenesis, impinging on the BMP-Runx2 pathway (Jeong et al., 2009), we also found that knockdown of ERRγ in calvarial cell cultures increases osteoblast differentiation and bone nodule formation. To extend our in vitro findings to the whole animal level, we have utilized an ERRγ knockout line (Deltagen). Whole mount skeletal preparations of late embryonic/early postnatal stages revealed an increase in intramembraneous bone formation, but no significant difference in long bone length. By μCT, we determined that several trabecular bone parameters are increased in 14 week and 6 month-old heterozygous male mice, and at 6 months there is also a significant decrease in SMI (indicative of a more plate-like trabecular structure) and a decrease in trabecular number. qPCR on mRNA isolated from trabecular bone of heterozygous 2 month-old male mice revealed an increase in osteoblast markers Osx, Alp and Bsp, as well as RankL and cathepsin K (Ctsk), markers of osteoclast differentiation and activity, respectively, suggesting an increase in bone turnover in ERRγ +/- compared to WT mice. To investigate the underlying cellular mechanisms, femoral bone marrow cells were isolated from 2 month-old male mice and cultured under osteoblast differentiation conditions. ALP- and von Kossa-positive colonies (number and area) were increased in ERRγ +/- compared to WT cultures. In silico analysis for ERRE consensus sequences identified Alp, Bsp, and Ctsk as putative ERRγ target genes. Collectively, our data indicate that ERRγ is a negative regulator of osteoblasts and osteoclasts, and further experiments are in progress to define how ERRγ impinges on the osteoblast-osteoclast signaling axis.

    Disclosures: None

    * Presenting Authors(s): Marco Cardelli, University of Toronto, CANADA