Zfhx4 regulates endochondral ossification as the transcriptional platform of Osterix in mice

ABSTRACT: Endochondral ossification is regulated by transcription factors that include SRY-box transcription factor 9, runt-related protein 2 (Runx2), and Osterix. However, the sequential and harmonious regulation of the multiple steps of endochondral ossification is unclear. This study identified zinc finger homeodomain 4 (Zfhx4) as a crucial transcriptional partner of Osterix. We found that Zfhx4 was highly expressed in cartilage and that Zfhx4 deficient mice had reduced expression of matrix metallopeptidase 13 and inhibited calcification of cartilage matrices. These phenotypes were very similar to impaired chondrogenesis in Osterix deficient mice. Coimmunoprecipitation and immunofluorescence indicated a physical interaction between Zfhx4 and Osterix. Notably, Zfhx4 and Osterix double mutant mice showed more severe phenotype than Zfhx4 deficient mice. Additionally, Zfhx4 interacted with Runx2 that functions upstream of Osterix. Our findings suggest that Zfhx4 coordinates the transcriptional network of Osterix and, consequently, endochondral ossification. Nakamura et al. used expression studies to identify an enrichment of Zfhx4 in cartilage and revealed through global gene knock-down that it is required for proper endochondral ossification in mice. They further demonstrated a physical and genetic interaction between Zfhx4 and Osterix, which is of interest to the field of transcriptional regulation of mammalian endochondral ossification.

SUBMITTER: Nakamura E 

PROVIDER: S-EPMC8566502 | biostudies-literature |

REPOSITORIES: biostudies-literature