Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Dev Cell. 2012 May 15;22(5):927-39. doi: 10.1016/j.devcel.2012.03.011.
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.
在软骨内骨化过程中，小而不成熟的软骨细胞增大形成肥大的软骨细胞，表达胶原 X。在这项工作中，我们证明 FoxA 因子在软骨发生过程中被诱导，与胶原 X 增强子中的保守结合位点结合，并能促进软骨细胞和成纤维细胞中胶原 X-荧光素酶报告基因的表达。此外，我们通过功能获得和功能丧失分析证明，FoxA 因子在驱动内源性胶原 X 和其他肥大软骨细胞特异性基因的表达中起着关键作用。在软骨细胞中缺乏 FoxA2 和 FoxA3 表达的小鼠在胸骨的软骨细胞肥大、碱性磷酸酶表达和矿化方面表现出缺陷，此外，还表现出出生后矮小症，与生长板中胶原 X 和 MMP13 的表达明显减少有关。我们的研究结果表明，FoxA 家族成员是肥大软骨细胞分化程序的关键调节因子。
