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.

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Authors

Ionescu A, Kozhemyakina E, Nicolae C, Kaestner KH, Olsen BR, Lassar AB

Institution

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Source

Developmental cell 22:5 2012 May 15 pg 927-39

MeSH

Alkaline Phosphatase
Animals
Binding Sites
Cell Differentiation
Cell Enlargement
Cells, Cultured
Chick Embryo
Chondrocytes
Chondrogenesis
Collagen Type X
Core Binding Factor Alpha 1 Subunit
Dwarfism
Embryo, Mammalian
Fibroblasts
Genes, Reporter
Growth Plate
Hepatocyte Nuclear Factor 3-beta
Hepatocyte Nuclear Factor 3-gamma
Matrix Metalloproteinase 13
Metatarsal Bones
Mice
Mice, Mutant Strains
Myogenic Regulatory Factors
Smad1 Protein

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22595668