title: FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program.
abstract: During endochondral ossification, small, immature chondrocytes enlarge to form hypertrophic chondrocytes, which express collagen X. In this work, we demonstrate that FoxA factors are induced during chondrogenesis, bind to conserved binding sites in the collagen X enhancer, and can promote the expression of a collagen X-luciferase reporter in both chondrocytes and fibroblasts. In addition, we demonstrate by both gain- and loss-of-function analyses that FoxA factors play a crucial role in driving the expression of both endogenous collagen X and other hypertrophic chondrocyte-specific genes. Mice engineered to lack expression of both FoxA2 and FoxA3 in their chondrocytes display defects in chondrocyte hypertrophy, alkaline phosphatase expression, and mineralization in their sternebrae and, in addition, exhibit postnatal dwarfism that is coupled to significantly decreased expression of both collagen X and MMP13 in their growth plates. Our findings indicate that FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andreia
authors.initials: A
authors.lastname: Ionescu
authors.forename: Elena
authors.initials: E
authors.lastname: Kozhemyakina
authors.forename: Claudia
authors.initials: C
authors.lastname: Nicolae
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Olsen
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lassar
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D049108:Cell Enlargement; D002478:Cells, Cultured; D002642:Chick Embryo; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D020219:Chondrogenesis / Q000235:genetics*; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004392:Dwarfism / Q000196:embryology / Q000235:genetics*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017930:Genes, Reporter; D006132:Growth Plate / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D008682:Metatarsal Bones / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D051898:Smad1 Protein / Q000378:metabolism
chemical_list: D024121:Collagen Type X; D050659:Core Binding Factor Alpha 1 Subunit; C496503:Foxa2 protein, mouse; C496506:Foxa3 protein, mouse; D018006:Myogenic Regulatory Factors; D051898:Smad1 Protein; D051543:Hepatocyte Nuclear Factor 3-gamma; D051542:Hepatocyte Nuclear Factor 3-beta; D000469:Alkaline Phosphatase; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse