PTHrP rescues ATDC5 cells from apoptosis induced by FGF receptor 3 mutation
| Autor: | Hiroyuki Tanaka, Mio Koike, Yoshitaka Yamanaka, Riko Nishimura, Yoshiki Seino |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
musculoskeletal diseases
medicine.medical_specialty Programmed cell death Endocrinology Diabetes and Metabolism Apoptosis DNA laddering Biology DNA Mitochondrial Chondrocyte Achondroplasia Cell Line Chondrocytes Osteogenesis Internal medicine medicine In Situ Nick-End Labeling Humans Receptor Fibroblast Growth Factor Type 3 Orthopedics and Sports Medicine Northern blot TUNEL assay Parathyroid Hormone-Related Protein Protein-Tyrosine Kinases musculoskeletal system Receptors Fibroblast Growth Factor Cell biology Genes bcl-2 Enzyme Activation medicine.anatomical_structure Endocrinology Cell culture Mutation Signal transduction Cell Division |
| Zdroj: | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 18(8) |
| ISSN: | 0884-0431 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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