Abstract |
A S252W mutation of fibroblast growth factor receptor 2 (FGFR2), which is responsible for nearly two-thirds of Apert syndrome (AS) cases, causes retarded development of the skeleton and skull malformation resulting from premature fusion of the craniofacial sutures. We utilized a Fgfr2(+/S252W) mouse (a knock-in mouse model mimicking human AS) to demonstrate decreased bone mass due to reduced trabecular bone volume, reduced bone mineral density, and shortened growth plates in the long bones. In vitro bone mesenchymal stem cells (BMSCs) culture studies revealed that the mutant mice showed reduced BMSC proliferation, a reduction in chondrogenic differentiation, and reduced mineralization. Our results suggest that these phenomena are caused by up-regulation of p38 and Erk1/2 phosphorylation. Treatment of cultured mutant bone rudiments with SB203580 or PD98059 resulted in partial rescue of the bone growth retardation. The p38 signaling pathway especially was found to be responsible for the retarded long bone development. Our data indicate that the S252W mutation in FGFR2 directly affects endochondral ossification, resulting in growth retardation of the long bone. We also show that the p38 and Erk1/2 signaling pathways partially mediate the effects of the S252W mutation of FGFR2 on long bone development.
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Authors | Peng Chen, Li Zhang, Tujun Weng, Shichang Zhang, Shijin Sun, Mingtao Chang, Yang Li, Bo Zhang, Lianyang Zhang |
Journal | PloS one
(PLoS One)
Vol. 9
Issue 1
Pg. e87311
( 2014)
ISSN: 1932-6203 [Electronic] United States |
PMID | 24489893
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Flavonoids
- Imidazoles
- Pyridines
- Receptor, Fibroblast Growth Factor, Type 2
- SB 203580
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Topics |
- Acrocephalosyndactylia
(genetics, pathology)
- Animals
- Cell Differentiation
(genetics)
- Embryonic Development
(genetics)
- Flavonoids
(pharmacology)
- Gene Knock-In Techniques
- Humans
- Imidazoles
(pharmacology)
- Mesenchymal Stem Cells
- Mice
- Mice, Inbred C57BL
- Mutation
- Osteogenesis
(genetics)
- Phosphorylation
- Pyridines
(pharmacology)
- Receptor, Fibroblast Growth Factor, Type 2
(genetics, metabolism, physiology)
- Signal Transduction
- Up-Regulation
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