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TACC3 facilitates chondrocyte differentiation by attenuating abnormally activated FGFR3 signaling in achondroplasia -
Xiang Li1, Long Bao2, Xiaoyan Wang1
1Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Soochow University, Suzhou, Jiangsu, China.
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.
Insights
TACC3 inhibition promotes chondrocyte differentiation in FGFR3 mutant cells, suggesting it is a potential therapeutic target for achondroplasia, a common form of dwarfism.
Area of Science:
- Cell Biology
- Skeletal Biology
- Molecular Genetics
Background:
- Achondroplasia, a common dwarfism, stems from fibroblast growth factor receptor 3 (FGFR3) mutations.
- FGFR3 mutations disrupt chondrocyte proliferation and differentiation, crucial for bone development.
Purpose of the Study:
- Investigate the mechanism behind FGFR3 mutation-induced defects in chondrocyte differentiation.
- Identify potential therapeutic targets for achondroplasia.
Main Methods:
- Utilized ATDC5 cells stimulated with insulin-transferrin-selenium (ITS-G) as an in vitro model.
- Assessed chondrocyte differentiation via Alcian Blue staining and gene expression analysis (ACAN, COL2A1).
- Examined the role of TACC3 and the p38 signaling pathway using a TACC3 inhibitor (KHS101) and a p38 inhibitor.
Main Results:
- FGFR3 mutations inhibited ITS-G-induced chondrocyte differentiation, decreasing ACAN and COL2A1 expression.
- TACC3 expression was modulated by FGFR3 activity; its inhibition (KHS101) promoted differentiation in mutant cells.
- The p38 signaling pathway was implicated, as KHS101 enhanced p38 expression, and p38 inhibition counteracted KHS101's pro-differentiation effects.
Conclusions:
- TACC3 plays a role in FGFR3 mutation-associated chondrocyte differentiation defects, potentially via the p38 signaling pathway.
- TACC3 inhibition presents a promising therapeutic strategy for achondroplasia.
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