TACC3 facilitates chondrocyte differentiation by attenuating abnormally activated FGFR3 signaling in achondroplasia - An in vitro study.

BACKGROUND

Achondroplasia is a common form of dwarfism. It is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3), which inhibits chondrocyte proliferation and differentiation.

AIM: In this study, we intended to investigate the underlying mechanism of FGFR3 mutation-induced chondrocyte differentiation defection.

METHOD: Insulin-transferrin-selenium (ITS-G) stimulated ATDC5 cells was used as an in vitro model. Alcian Blue staining was performed to detect ATDC5 cell differentiation.

RESULTS

TACC3 expression was increased during ATDC5 cell differentiation. ITS-G induced ATDC5 cell differentiation was inhibited by the FGFR3 mutation, as evidenced by the decreased expression of ACAN and COL2A1. The downregulation of TACC3 expression induced by ITS-G stimulation was upregulated by FGFR3 overactivation. The TACC3 inhibitor (KHS101) promoted differentiation in FGFR3 mutant ATDC5 cells. The p38 signaling pathway has been implicated in FGFR3 mutation-induced chondrocyte differentiation defects. KHS101 promoted the expression of p38. KHS101-induced increase in ATDC5 cell differentiation was inhibited by the administration of a p38 inhibitor. These results suggest that TACC3 might play a role through the p38 signaling pathway in chondrocyte differentiation defects caused by FGFR3 mutations.

CONCLUSION

TACC3 might represent a novel target for achondroplasia.