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The Orphan Nuclear Estrogen Receptor-Related Receptor- Regulates Cartilage Formation in Vitro: Implication of Sox9

Department of Molecular and Medical Genetics (E.B., R.A.Z., J.E.A.), University of Toronto, Toronto, Ontario, Canada M5S 1A8; Laboratoire de Biologie Moleculaire de la Cellule (E.B., P.J.), Institut Fédératif de Recherche 128 Biosciences Lyon-Gerland École Normale Supérieure/Centre National de la Recherche Scientifique 5161, 69365 Lyon, France; and Mécanismes et Traitements des Métastases Osseuses des Tumeurs Solides (E.B.), Unité Institut National de la Santé et de la Recherche Médicale Unité 664, Faculté de Médecine René Théophile-Hyacinthe Laennec, 69372 Lyon, France

Address all correspondence and requests for reprints to: Jane E. Aubin, Ph.D., Department of Molecular and Medical Genetics, Faculty of Medicine, University of Toronto, Room 6230, Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: jane.aubin{at}utoronto.ca.

We report for the first time the expression of estrogen receptor-related receptor (ERR)- in fetal and adult rat chondrocytes in growth plate and articular cartilage and the rat chondrogenic cell line C5.18 cells in vitro. ERR mRNA and protein were expressed from proliferating chondrocyte to mature chondrocyte stages. We show that overexpressing ERR in C5.18 cell cultures induces an increase in Sry-type high-mobility-group box transcription factor (Sox)-9 expression, a master gene in cartilage formation. In parallel, we report Sox9 promoter regulation by ERR in C5.18 cells. To assess a functional role for ERR in chondrogenesis, its expression was blocked by antisense oligonucleotides in C5.18 cell cultures, and this led to inhibition of cartilage formation associated with down-regulation of Sox9 and Indian hedgehog expression and maturation of proliferating chondrocytes into hypertrophic chondrocytes in vitro. Together these results implicate ERR in the formation and maintenance of cartilage and also suggest that agonists and antagonists of ERR may be useful as therapeutic agents in a wide variety of diseases affecting cartilage and joints.

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