title: Cartilage-specific overexpression of ERRγ results in Chondrodysplasia and reduced chondrocyte proliferation.
abstract: While the role of estrogen receptor-related receptor alpha (ERRα) in chondrogenesis has been investigated, the involvement of ERR gamma (ERRγ) has not been determined. To assess the effect of increased ERRγ activity on cartilage development in vivo, we generated two transgenic (Tg) lines overexpressing ERRγ2 via a chondrocyte-specific promoter; the two lines exhibited ∼3 and ∼5 fold increased ERRγ2 protein expression respectively in E14.5 Tg versus wild type (WT) limbs. On postnatal day seven (P7), we observed a 4-10% reduction in the size of the craniofacial, axial and appendicular skeletons in Tg versus WT mice. The reduction in bone length was already present at birth and did not appear to involve bones that are derived via intramembranous bone formation as the bones of the calvaria, clavicle, and the mandible developed normally. Histological analysis of P7 growth plates revealed a reduction in the length of the Tg versus WT growth plate, the majority of which was attributable to a reduced proliferative zone. The reduced proliferative zone paralleled a decrease in the number of Ki67-positive proliferating cells, with no significant change in apoptosis, and was accompanied by large cell-free swaths of cartilage matrix, which extended through multiple zones of the growth plate. Using a bioinformatics approach, we identified known chondrogenesis-associated genes with at least one predicted ERR binding site in their proximal promoters, as well as cell cycle regulators known to be regulated by ERRγ. Of the genes identified, Col2al, Agg, Pth1r, and Cdkn1b (p27) were significantly upregulated, suggesting that ERRγ2 negatively regulates chondrocyte proliferation and positively regulates matrix synthesis to coordinate growth plate height and organization.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Cardelli
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Zirngibl
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Boetto
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kristen P
authors.initials: KP
authors.lastname: McKenzie
authors.affiliation: Regenerative Medicine Program, Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Tammy-Claire
authors.initials: TC
authors.lastname: Troy
authors.affiliation: Regenerative Medicine Program, Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Kursad
authors.initials: K
authors.lastname: Turksen
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Aubin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002356:Cartilage / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology*; D020219:Chondrogenesis / Q000235:genetics; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005097:Exostoses, Multiple Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006132:Growth Plate / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism
chemical_list: C493961:Cdkn1b protein, mouse; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; C490916:Esrrg protein, mouse; D020033:Protein Isoforms; D044168:Receptor, Parathyroid Hormone, Type 1; D011960:Receptors, Estrogen; D050760:Cyclin-Dependent Kinase Inhibitor p27