 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Aug 25, 2024 |
| Title |
Effect of Col1a2 mutation in the gene expression of immature and mature osteoblasts in a mouse model of osteognesis imperfecta (OI) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
In Europe, approximately 85-90% of individuals with Osteogenesis Imperfecta (OI) have dominant pathogenic variants in the COL1A1 or COL1A2 genes whilst for Asian, especially Indian and Chinese cohorts, this ratio is much lower. This leads to decreased or abnormal Collagen type I production. Subsequently, bone formation is strongly reduced, causing bone fragility and liability to fractures throughout life. OI is clinically classified in 5 types with the severity ranging from mild to lethal depending on the gene and the type and location of the OI-causative variant and the subsequent effect on (pro) collagen type I synthesis. However, the specific effects on the phenotype and function of osteoblasts are not fully understood. To investigate this, the OI murine model was used, with the oim/oim (OIM) mice closest resembling severely deforming OI type 3 in humans. We showed that in OIM, COL1 mutation results in a multifactorial inhibition of the osteogenic differentiation and maturation as well as inhibition of osteoclastogenesis. The phenotype of differentiated OIM osteoblasts also differs from that of wild type mature osteoblasts, with upregulated oxidative cell stress and autophagy pathways, possibly in response to the intracellular accumulation of type I collagen mRNA. The extracellular accumulation of defective type I collagen fibres contributes to activation of the TGF- signalling pathway and activates the inflammatory pathway. These effects combine to destabilise the balance of bone turnover, increasing bone fragility. Together, these findings identify the complex mechanisms underlying OI bone fragility in the OIM model of severe OI and can potentially enable identification of clinically relevant endpoints to assess the efficacy of innovative pro-osteogenic treatment for patients with OI.
|
| |
|
| Overall design |
To propose a theoretical model of OI bone fragility, we used primary pre-osteoblasts isolated from the calvaria of homozygous OIM and wild type (WT) neonatal mice to determine the genetic impact of the recessive variant of Col1a2 on osteoblast phenotype during the process of osteogenic differentiation. The WT and OIM pre-osteoblasts were cultured for 21 days under osteogenic conditions and then RNA was isolated for transcriptomic analysis by RNAseq. 5 different groups of samples were compared: Group A (WT preosteoblasts or WTd0), Group B (WT differentiated osteoblast or WTd21); Group C (OIM pre-osteoblasts or OIMd0) and Group D (OIM differentiated osteoblast OIMd21). DEGs from sveral comparisons were Comparisons
|
| |
|
| Contributor(s) |
V Guillot P, Corcelli M |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Aug 01, 2024 |
| Last update date |
Aug 26, 2024 |
| Contact name |
Michelangelo Corcelli |
| E-mail(s) |
m.corcelli@ucl.ac.uk
|
| Phone |
07756750648
|
| Organization name |
UCL
|
| Street address |
Zayed Centre for Research, 20 Guilford Street, London,
|
| City |
London |
| State/province |
London |
| ZIP/Postal code |
WC1N 1DZ |
| Country |
United Kingdom |
| |
|
| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
|
| Samples (14)
|
|
| Relations |
| BioProject |
PRJNA1143048 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE273779_RAW.tar |
46.6 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
|
|
|
|
 |
Less...
More...