FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program.
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.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
SourceDevelopmental cell 22:5 2012 May 15 pg 927-39
Collagen Type X
Core Binding Factor Alpha 1 Subunit
Hepatocyte Nuclear Factor 3-beta
Hepatocyte Nuclear Factor 3-gamma
Matrix Metalloproteinase 13
Mice, Mutant Strains
Myogenic Regulatory Factors
Pub Type(s)Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't