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Updated: Aug 29, 2026
Laser Capture Microdissection of Mouse Embryonic Cartilage and Bone for Gene Expression Analysis
Published on: December 18, 2019
Molecular basis for the treatment of achondroplasia
Yoshitaka Yamanaka1, Koso Ueda, Yoshiki Seino
1Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. yamanaka@cc.okayama-u.ac.jp
Abstract:
Achondroplasia (ACH), the most common form of short-limbed dwarfism, and its related disorders are caused by constitutively activated point-mutated fibroblast growth factor receptor 3 (FGFR3). Recent studies have provided a large body of evidence to prove chondrocyte proliferation and differentiation in these disorders. However, little is known about the possible effects of the FGFR3 mutants on apoptosis of chondrocytes. In the present study, we analyzed apoptosis using a chondrogenic cell line, ATDC5, expressing the FGFR3 mutants causing ACH and thanatophoric dysplasia, which is a more severe neonatal lethal form comprising type I and type II. We found that the introduction of these mutated FGFR3s into ATDC5 cells decreased mRNA expression of parathyroid hormone-related peptide (PTHrP) and induced apoptosis. Importantly, replacement of PTHrP prevented the apoptotic changes in ATDC5 cells expressing ACH mutant. Insulin-like growth factor (IGF)-I, which is an important mediator of growth hormone (GH), also reduced apoptosis in ATDC5 cells expressing ACH mutant. IGF-I prevented apoptosis through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, indicating the mechanisms by which GH treatment improves disturbed bone growth in ACH.
Insights
Fibroblast growth factor receptor 3 (FGFR3) mutations in achondroplasia induce chondrocyte apoptosis. Parathyroid hormone-related peptide (PTHrP) replacement and insulin-like growth factor-I (IGF-I) treatment can prevent this, offering insights into growth hormone therapy.
Area of Science:
- Cell Biology
- Endocrinology
- Skeletal Dysplasias
Background:
- Achondroplasia (ACH) and related disorders stem from overactive fibroblast growth factor receptor 3 (FGFR3) mutations.
- While FGFR3's role in chondrocyte proliferation is known, its impact on chondrocyte apoptosis remains unclear.
Purpose of the Study:
- To investigate the effects of FGFR3 mutations on chondrocyte apoptosis.
- To explore potential therapeutic interventions for FGFR3-related skeletal disorders.
Main Methods:
- Utilized the ATDC5 chondrogenic cell line engineered to express FGFR3 mutants linked to ACH and thanatophoric dysplasia.
- Assessed apoptosis, mRNA expression of parathyroid hormone-related peptide (PTHrP), and the impact of PTHrP and insulin-like growth factor-I (IGF-I) replacement.
Main Results:
- FGFR3 mutants in ATDC5 cells reduced PTHrP mRNA expression and triggered apoptosis.
- Restoring PTHrP levels mitigated apoptosis in cells with the ACH mutant.
- IGF-I significantly reduced apoptosis in ACH mutant cells via phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways.
Conclusions:
- FGFR3 mutations promote chondrocyte apoptosis, partly by downregulating PTHrP.
- IGF-I demonstrates a protective effect against apoptosis in FGFR3-mutant chondrocytes through specific signaling pathways.
- Findings suggest mechanisms underlying growth hormone therapy's efficacy in ACH and related conditions.
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