論文 - 詳細
| RRC ID | 41948 |
|---|---|
| 著者 | Yamanaka Y, Tanaka H, Koike M, Nishimura R, Seino Y. |
| タイトル | PTHrP rescues ATDC5 cells from apoptosis induced by FGF receptor 3 mutation. |
| ジャーナル | J Bone Miner Res |
| Abstract |
UNLABELLED:An activation mutation in the FGFR3 gene causes ACH. The effects of the FGFR3 mutants on apoptosis were analyzed in a chondrogenic cell line. ACH chondrocytes exhibited marked apoptotic with downregulation of PTHrP expression. Rescue of these cells by PTHrP replacement implies a potential therapy for this disorder. INTRODUCTION:Achondroplasia (ACH), the most common form of short-limb dwarfism, and its related disorders are caused by constitutively activated point-mutated FGFR3. Recent studies have provided a large body of evidence on chondrocyte proliferation and differentiation in these disorders. However, little is known about the possible effects of the FGFR3 mutants on apoptosis of chondrocytes. METHODS:The mutant FGFR3 genes causing ACH and thanatophoric dysplasia (TD), which is a more severe neonatal lethal form, were introduced into a chondrogenic cell line, ATDC5. Analysis of apoptosis was estimated by TUNEL assay, DNA laddering, and fluorescent measurement of mitochondrial membrane potential. Expression levels of parathyroid hormone-related peptide (PTHrP) and apoptosis-related genes were analyzed by Northern blot or immunoblot. RESULTS:The introduction of these mutated FGFR3s into ATDC5 cells downregulated PTHrP expression and induced apoptosis with reduction of Bcl-2 expression. Importantly, replacement of PTHrP prevented the apoptotic changes and reduction of Bcl-2 expression in ATDC5 cells expressing the ACH mutant. In parallel with the severity of disease and the activity of FGFR3, ATDC5 cells expressing TD-mutant FGFR3 showed less expression of PTHrP and Bcl-2 and induced more remarkable apoptotic changes compared with ACH-mutant expressing cells. Furthermore, overexpression of Bcl-2 inhibited apoptotic changes, suggesting that the mutant FGFR3 caused apoptosis, at least in part, through reduction of Bcl-2 expression, which seems to be downstream of PTHrP. CONCLUSIONS:Our data suggest that excessive activation of signaling cascades mediated by the FGFR3 mutants inhibits the expression of PTHrP and Bcl-2, resulting in apoptosis of chondrocytes, possibly leading to short-limb dwarfism. Rescue of these cells by PTHrP replacement implies a potential therapy for this disorder. |
| 巻・号 | 18(8) |
| ページ | 1395-403 |
| 公開日 | 2003-8-1 |
| DOI | 10.1359/jbmr.2003.18.8.1395 |
| PMID | 12929929 |
| MeSH | Achondroplasia / genetics Achondroplasia / metabolism Achondroplasia / pathology Apoptosis / physiology* Cell Division Cell Line Chondrocytes / cytology Chondrocytes / metabolism DNA, Mitochondrial / genetics Enzyme Activation Genes, bcl-2 / genetics Genes, bcl-2 / physiology Humans In Situ Nick-End Labeling Mutation / genetics* Osteogenesis Parathyroid Hormone-Related Protein / metabolism* Protein-Tyrosine Kinases / metabolism Receptor, Fibroblast Growth Factor, Type 3 Receptors, Fibroblast Growth Factor / genetics* Receptors, Fibroblast Growth Factor / metabolism* |
| IF | 5.854 |
| 引用数 | 18 |
| WOS 分野 | ENDOCRINOLOGY & METABOLISM |
| リソース情報 | |
| ヒト・動物細胞 | ATDC5(RCB0565) |