JMJD3 promotes chondrocyte proliferation and hypertrophy during endochondral bone formation in mice

JMJD3 (KDM6B) is an H3K27me3 demethylaseand counteracts polycomb-mediated transcription repression. However, the function of JMJD3 in vivo is not well understood. Here we show that JMJD3 is highly expressed in cells of the chondrocytelineage, especially in prehypertrophic and hypertrophic chondrocytes, during endochondral ossification. Homozygous deletion of Jmjd3 results in severely decreased proliferation and delayed hypertrophy of chondrocytes, and thereby marked retardation of endochondral ossificationin mice. Genetically, JMJD3 associates with RUNX2to promote proliferation and hypertrophy of chondrocytes. Biochemically, JMJD3 associates with and enhances RUNX2activity by derepressionof Runx2and Ihh transcription through its H3K27me3 demethylaseactivity. These results demonstrate that JMJD3 is a key epigenetic regulator in the process of cartilage maturation during endochondral bone formation.