Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the Apert syndrome FGFR2(S252W/+) mice.
Apert syndrome (AS) is a type of autosomal dominant disease characterized by premature fusion of the cranial sutures, severe syndactyly, and other abnormalities in internal organs. Approximately 70% of AS cases are caused by a single mutation, S252W, in fibroblast growth factor receptor 2 (FGFR2). T...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4333342?pdf=render |
| _version_ | 1819064739717709824 |
|---|---|
| author | Li Zhang Peng Chen Lin Chen Tujun Weng Shichang Zhang Xia Zhou Bo Zhang Luchuan Liu |
| author_facet | Li Zhang Peng Chen Lin Chen Tujun Weng Shichang Zhang Xia Zhou Bo Zhang Luchuan Liu |
| author_sort | Li Zhang |
| collection | DOAJ |
| description | Apert syndrome (AS) is a type of autosomal dominant disease characterized by premature fusion of the cranial sutures, severe syndactyly, and other abnormalities in internal organs. Approximately 70% of AS cases are caused by a single mutation, S252W, in fibroblast growth factor receptor 2 (FGFR2). Two groups have generated FGFR2 knock-in mice Fgfr2S252W/+ that exhibit features of AS. During the present study of AS using the Fgfr2S252W/+ mouse model, an age-related phenotype of bone homeostasis was discovered. The long bone mass was lower in 2 month old mutant mice than in age-matched controls but higher in 5 month old mutant mice. This unusual phenotype suggested that bone marrow-derived mesenchymal stem cells (BMSCs), which are vital to maintain bone homeostasis, might be involved. BMSCs were isolated from Fgfr2S252W/+ mice and found that S252W mutation could impair osteogenic differentiation BMSCs but enhance mineralization of more mature osteoblasts. A microarray analysis revealed that Wnt pathway inhibitors SRFP1/2/4 were up-regulated in mutant BMSCs. This work provides evidence to show that the Wnt/β-catenin pathway is inhibited in both mutant BMSCs and osteoblasts, and differentiation defects of these cells can be ameliorated by Wnt3a treatment. The present study suggested that the bone abnormalities caused by deregulation of Wnt pathway may underlie the symptoms of AS. |
| first_indexed | 2024-12-21T15:35:22Z |
| format | Article |
| id | doaj.art-885757d0fec74ca8ac5f0d437463ba9d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T15:35:22Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-885757d0fec74ca8ac5f0d437463ba9d2022-12-21T18:58:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01102e11271610.1371/journal.pone.0112716Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the Apert syndrome FGFR2(S252W/+) mice.Li ZhangPeng ChenLin ChenTujun WengShichang ZhangXia ZhouBo ZhangLuchuan LiuApert syndrome (AS) is a type of autosomal dominant disease characterized by premature fusion of the cranial sutures, severe syndactyly, and other abnormalities in internal organs. Approximately 70% of AS cases are caused by a single mutation, S252W, in fibroblast growth factor receptor 2 (FGFR2). Two groups have generated FGFR2 knock-in mice Fgfr2S252W/+ that exhibit features of AS. During the present study of AS using the Fgfr2S252W/+ mouse model, an age-related phenotype of bone homeostasis was discovered. The long bone mass was lower in 2 month old mutant mice than in age-matched controls but higher in 5 month old mutant mice. This unusual phenotype suggested that bone marrow-derived mesenchymal stem cells (BMSCs), which are vital to maintain bone homeostasis, might be involved. BMSCs were isolated from Fgfr2S252W/+ mice and found that S252W mutation could impair osteogenic differentiation BMSCs but enhance mineralization of more mature osteoblasts. A microarray analysis revealed that Wnt pathway inhibitors SRFP1/2/4 were up-regulated in mutant BMSCs. This work provides evidence to show that the Wnt/β-catenin pathway is inhibited in both mutant BMSCs and osteoblasts, and differentiation defects of these cells can be ameliorated by Wnt3a treatment. The present study suggested that the bone abnormalities caused by deregulation of Wnt pathway may underlie the symptoms of AS.http://europepmc.org/articles/PMC4333342?pdf=render |
| spellingShingle | Li Zhang Peng Chen Lin Chen Tujun Weng Shichang Zhang Xia Zhou Bo Zhang Luchuan Liu Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the Apert syndrome FGFR2(S252W/+) mice. PLoS ONE |
| title | Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the Apert syndrome FGFR2(S252W/+) mice. |
| title_full | Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the Apert syndrome FGFR2(S252W/+) mice. |
| title_fullStr | Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the Apert syndrome FGFR2(S252W/+) mice. |
| title_full_unstemmed | Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the Apert syndrome FGFR2(S252W/+) mice. |
| title_short | Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the Apert syndrome FGFR2(S252W/+) mice. |
| title_sort | inhibited wnt signaling causes age dependent abnormalities in the bone matrix mineralization in the apert syndrome fgfr2 s252w mice |
| url | http://europepmc.org/articles/PMC4333342?pdf=render |
| work_keys_str_mv | AT lizhang inhibitedwntsignalingcausesagedependentabnormalitiesinthebonematrixmineralizationintheapertsyndromefgfr2s252wmice AT pengchen inhibitedwntsignalingcausesagedependentabnormalitiesinthebonematrixmineralizationintheapertsyndromefgfr2s252wmice AT linchen inhibitedwntsignalingcausesagedependentabnormalitiesinthebonematrixmineralizationintheapertsyndromefgfr2s252wmice AT tujunweng inhibitedwntsignalingcausesagedependentabnormalitiesinthebonematrixmineralizationintheapertsyndromefgfr2s252wmice AT shichangzhang inhibitedwntsignalingcausesagedependentabnormalitiesinthebonematrixmineralizationintheapertsyndromefgfr2s252wmice AT xiazhou inhibitedwntsignalingcausesagedependentabnormalitiesinthebonematrixmineralizationintheapertsyndromefgfr2s252wmice AT bozhang inhibitedwntsignalingcausesagedependentabnormalitiesinthebonematrixmineralizationintheapertsyndromefgfr2s252wmice AT luchuanliu inhibitedwntsignalingcausesagedependentabnormalitiesinthebonematrixmineralizationintheapertsyndromefgfr2s252wmice |