An inducible mouse model of OI type V reveals aberrant osteogenesis caused by Ifitm5 c.-14C>T mutation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1103117 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28764490.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 1 of 1 |
Similar Datasets
Project description:Osteogenesis imperfecta (OI) Type V is typically characterized by radial head dislocation, calcification of interosseous membrane and post-fracture hyperplastic callus. It is caused by the c.-14C>T mutation in the 5’UTR of the IFITM5 gene, adding five amino acids (MALEP) to the N-terminal of IFITM5 protein. Previous studies have suggested a neomorphic function of the MALEP-IFITM5 protein. However, the underlying mechanisms remain unclear due to embryonic lethality in previous models. Therefore, we developed an inducible animal model of Ifitm5flox c.-14C>T that could be induced by Cre expressing at different developmental stages to explore the pathogenic effects of the neomorphic MALEP-IFITM5. Specifically, Prx1-Cre; Ifitm5flox c.-14C>T mutant mice were born with fractures in all limbs, showing deficient ossification and enhanced chondrogenesis associated with increased SOX9 abundance. We isolated skeletal cells from tibia of Ifitm5 mutant mouse at P6 stage and conducted single RNA sequencing (10X Genomics). The data were compared to the RNA-seq data generated from the tibia of control mouse at the same stage (GSE159544).
2025-02-20 | GSE264540 | GEO
Project description:Osteogenesis imperfecta (OI) is a serious genetic bone disorder characterized by congenital low bone mass, deformity and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 mutations. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 mutations and found the proportion of type XV patients was around 10.3% (25 out of 243) with diverse phenotypic spectrums. Functional assays indicated that mutations of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST was dramatically reduced in type XV patients. Single-cell transcriptome data generated from human tibia samples revealed aberrant differentiation trajectory of skeletal progenitors and impaired maturation of osteocytes, resulting in excessive CXCL12+ progenitors and abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV osteogenesis imperfecta and relative low bone mass diseases such as early onset osteoporosis.
2024-10-17 | PXD050841 | Pride
Project description:Osteogenesis imperfecta (OI) is a serious genetic bone disorder characterized by congenital low bone mass, deformity and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 mutations. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 mutations and found the proportion of type XV patients was around 10.3% (25 out of 243) with diverse phenotypic spectrums. Functional assays indicated that mutations of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST was dramatically reduced in type XV patients. Single-cell transcriptome data generated from human tibia samples revealed aberrant differentiation trajectory of skeletal progenitors and impaired maturation of osteocytes, resulting in excessive CXCL12+ progenitors and abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV osteogenesis imperfecta and relative low bone mass diseases such as early onset osteoporosis.
2024-08-13 | GSE262092 | GEO
Project description:Osteogenesis imperfecta (OI) is a serious genetic bone disorder characterized by congenital low bone mass, deformity and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 mutations. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 mutations and found the proportion of type XV patients was around 10.3% (25 out of 243) with diverse phenotypic spectrums. Functional assays indicated that mutations of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST was dramatically reduced in type XV patients. Single-cell transcriptome data generated from human tibia samples revealed aberrant differentiation trajectory of skeletal progenitors and impaired maturation of osteocytes, resulting in excessive CXCL12+ progenitors and abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV osteogenesis imperfecta and relative low bone mass diseases such as early onset osteoporosis.
2024-08-13 | GSE262091 | GEO
Project description:Osteogenesis imperfecta (OI) is a group of diseases caused by defects in type I collagen processing which result in skeletal fragility. While these disorders have traditionally been regarded as defects in osteoblast function, the role of matrix-embedded osteocytes, descendants of osteoblasts, in OI pathogenesis remains unknown. The homozygous human SP7 (c.946C > T, R316C) mutation results in a recessive form of osteogenesis imperfecta characterized by short stature, fragility fractures, low bone mineral density, and osteocyte dendrite defects. To better understand how the osteogenesis imperfecta-causingSP7 R316Cmutation affects the function of this transcription factor in different osteoblast lineage cells in bone, we generatedSp7 R342Cknock-in mice. Homozygous mutantSp7 R342C/R342Cmice demonstrate increased cortical porosity and reduced cortical bone mineral density, findings consistent with phenotypes observed in patients with this mutation. Sp7 R342Cmice show osteocyte dendrite defects, increased osteocyte apoptosis, and intracortical bone remodeling characterized by ectopic intracortical osteoclasts and elevated Tnfsf11 expression by osteocytes. Remarkably, these overt defects in osteocyte function contrast to preserved osteoblast function, suggesting that this Sp7 point mutation selectively interferes with the function of this transcription factor in osteocytes but not osteoblasts. Osteocyte morphology changes in Sp7 R342C/R342Cmice were not restored by inhibiting osteoclast formation, indicating that dendrite defects lie upstream of high intra-cortical osteoclast activity in this model. Moreover, transcriptomic profiling reveals that the expression of a core set osteocyte-enriched genes is highly dysregulated by the R342C mutation. Thus, this model supports a model in which osteocyte dysfunction can drive osteogenesis imperfecta pathogenesis, and provides a valuable resource to test novel therapeutic approaches and to understand the osteocyte-specific role of SP7 in bone homeostasis and remodeling.
2025-05-16 | GSE270443 | GEO
Project description:Anti-Transforming growth factor beta (TGF-β) is a promising approach for the treatment of osteogenesis imperfecta (OI). To date, preclinical and clinical studies for the use of anti-TGF-β therapy have focused on moderate to severe OI caused by qualitative defects in collagen. However, the majority of OI patients are represented by type I OI. Haploinsufficiency of type I collagen causes OI type I. To study the effect of anti-TGF-β therapy in type I OI, we generated novel mouse model for OI type I. CMV-CRE mice were crossed to mice where Col1a1 was floxed between exon 2 and 5 to create a full body heterozygous deletion of Col1a1. Haploinsufficiency in the tibia was confirmed by decreased Col1a1 mRNA and protein expression. Comparable to OI patients, we observed reduced bone mass by μCT in these Col1a1+/- mice. Biomechanical measurements showed a decrease in bone strength and an increase in bone brittleness. Histomorphometric analysis showed an increase in osteoclast number and a trend towards increased osteoblasts. Overall suggesting this mouse shows a phenotype overlapping with OI type I. Upon treatment with a pan anti-TGF-β antibody, 1D11, this mouse model of OI type I showed increased bone mass. anti-TGF-β treatment further improved ultimate strength in the Col1a1+/- mice, but measures of ductility did not show improvement. Overall, our findings support expanding research on anti-TGFβ treatment for OI to OI caused by haploinsufficiency for type I collagen.
2025-05-07 | GSE293448 | GEO
Project description:Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes in addition to bone fragility. All patients carry a dominant pathogenic variant (c.-14C>T) in IFITM5. Here, we generated a conditional Rosa26 knock-in mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in OI type V patients. Surprisingly, expression of mutant Ifitm5 in matrix-synthesizing or mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with increase in the skeletal progenitor population within the periosteum. Mutant IFITM5 disrupts early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. . Tracing of chondrogenic cells expressing the mutant Ifitm5 using the Ai9 reporter showed retention of Ai9+ cells in the growth plate and delayed migration to the bone shaft. RNA sequencing demonstrated enrichment for chondrogenic markers in the bone. These data identify the contribution of a defect in osteo-chondroprogenitor differentiation and not osteoblast function as a driver in the pathogenesis of OI type V.
2024-07-23 | GSE268601 | GEO
Project description:Collagen misfolding, reduced collagen secretion and incorporation into the extracellular matrix, and impaired collagen organization are common features both in a physiological condition like aging and in pathological conditions like genetic diseases caused by defects in collagen or collagen related genes. Osteogenesis imperfecta (OI) is the prototype of collagen disorders since it is mainly caused by mutations in genes responsible for the synthesis and post translational modification of collagen type I, the most abundant protein of our body and of our skeleton. OI probands show reduced bone mass, bone deformations, and increased bone fragility associated to frequent fractures, but they do not benefit from specific treatments. Here the therapeutic potential of heat shock protein 47 (HSP47), the collagen specific chaperone and a key endogenous player in collagen secretion, was tested in OI probands primary fibroblast lines. Administration of exogenous HSP47, that is able to be uptaken by the cell and to localize with both cis Golgi and secretory pathway sites, increased collagen secretion, reduced intracellular procollagen I retention and ameliorated the general ER proteostasis, leading to a substantial improvement in cellular homeostasis and vitality. These positive changes were also mirrored by an increased content into the OI proband matrix of collagen I. Efficacy of exogenous HSP47 was then proved in vivo on the bone phenotype of the zebrafish p3h1-/- OI model. Methods Collection samples nLC‑MS/MS analysis was used to assess hydroxylation and O-Glycosylation on lysine sites of type I collagen. Extracted collagen from control, OI and HS47 probands fibroblasts were separated by SDS-PAGE and stained with colloidal Coomassie; the bands α(I) and α(II) (i.e., at the selected molecular mass values) were excised and destained in 0.1% TFA: ACN 1:1 (v/v).
2025-05-06 | PXD047320 | Pride
Project description:Osteogenesis imperfecta (OI) is most commonly caused by autosomal dominant mutations in genes encoding collagen type-I. Here, we test the hypothesis that modulation of the endoplasmic reticulum (ER) proteostasis network via the unfolded protein response (UPR) can improve the folding and secretion of the lethal osteogenesis imperfecta (OI)-causing G425S a1(I) variant. We show that specific induction of the UPR’s XBP1s transcriptional response enhances G425S a1(I) secretion up to ~300% of basal levels. Notably, the effect is selective – WT a1(I) secretion is unaltered by XBP1s. XBP1s pathway activation appears to post-translationally enhance the folding/assembly and secretion of G425S a1(I). Consistent with this notion, we find that the stable, triple-helical collagen-I secreted by XBP1s-activated G425S a1(I) patient fibroblasts includes a higher proportion of the mutant a1(I) polypeptide than the collagen-I secreted under basal ER proteostasis conditions.
2023-12-19 | GSE163812 | GEO
Project description:Osteogenesis imperfecta (OI) is a rare inherited connective tissue dysplasia characterized with skeletal fragility, recurrent fractures and bone deformity, predominantly caused by mutations in the genes COL1A1 or COL1A2 that encode the chains of type I collagen. In the present study, clinical manifestations and genetic variants were analysed from 188 Chinese OI patients, majority of which are of southern China origin. By targeted sequencing, 64 and 58 OI patients were found carrying mutations in COL1A1 and COL1A2 respectively, including 12 novel COL1A1 and 8 novel COL1A2 variants. We identified a COL1A1 hotspot (c.G2461A; p.G821S) in 8 patients and validated two novel splicing mutations. A diverse mutational and phenotypic spectrum was observed, coupling with heterogeneity observed in the transcriptomic data (n=6) derived from osteoblasts of our cohort. Missense mutations were significantly associated (χ2 p=0.0096) with a cluster of patients with more severe clinical phenotypes. Additionally, the severity of OI was more correlated with the quality of bones, rather than the bone mineral density. Bone density is most responsive to bisphosphonate (BP) treatment during the juvenile stage (10-15 y/o). In contrast, height is not responsive to bisphosphonate treatment. Our findings expand the mutational spectrum of type I collagen genes and the genotype-phenotype correlation in Chinese OI patients. The observation of effective BP treatment in an age-specific manner may help to improve OI patient management.
2022-01-10 | GSE186141 | GEO