Osteoclast-independent osteocyte dendrite defects in mice bearing the Osteogenesis Imperfecta-causing Sp7 R342C mutation
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PROVIDER: PRJNA1126646 | ENA |
REPOSITORIES: ENA
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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:Some cuboidal osteoblasts differentiate into bone-embedded, dendrite-bearing osteocytes through the poorly-understood process of osteocytogenesis. Here, we report that the transcription factor Sp7 plays an essential role in osteocytogenesis. Severe defects in bone integrity and osteocyte dendrite morphology are noted in mice lacking Sp7 at the stage of the osteoblast-to-osteocyte transition. In osteocytes, Sp7 controls expression of a neuronally-enriched gene network. Analysis of the osteocyte-specific Sp7 cistrome reveals distinct genomic binding motifs and target sites distinct from those in osteoblasts. Amongst osteocyte-specific Sp7 targets, the secreted peptide osteocrin rescues Sp7-deficient defects. Single-cell transcriptional profiling of cells undergoing osteocytogenesis identifies novel Sp7-dependent transitional cell types enriched in genes linked to human fracture risk. Finally, humans with an SP7 R316C mutation display osteocyte morphology defects similar to those observed in mouse models. These findings demonstrate that cuboidal osteoblasts use a neuronally-enriched Sp7/osteocrin gene expression program to differentiate into dendrite-bearing osteocytes.
2021-09-20 | GSE154717 | GEO
Project description:Some cuboidal osteoblasts differentiate into bone-embedded, dendrite-bearing osteocytes through the poorly-understood process of osteocytogenesis. Here, we report that the transcription factor Sp7 plays an essential role in osteocytogenesis. Severe defects in bone integrity and osteocyte dendrite morphology are noted in mice lacking Sp7 at the stage of the osteoblast-to-osteocyte transition. In osteocytes, Sp7 controls expression of a neuronally-enriched gene network. Analysis of the osteocyte-specific Sp7 cistrome reveals distinct genomic binding motifs and target sites distinct from those in osteoblasts. Amongst osteocyte-specific Sp7 targets, the secreted peptide osteocrin rescues Sp7-deficient defects. Single-cell transcriptional profiling of cells undergoing osteocytogenesis identifies novel Sp7-dependent transitional cell types enriched in genes linked to human fracture risk. Finally, humans with an SP7 R316C mutation display osteocyte morphology defects similar to those observed in mouse models. These findings demonstrate that cuboidal osteoblasts use a neuronally-enriched Sp7/osteocrin gene expression program to differentiate into dendrite-bearing osteocytes.
2021-09-20 | GSE154718 | GEO
Project description:Some cuboidal osteoblasts differentiate into bone-embedded, dendrite-bearing osteocytes through the poorly-understood process of osteocytogenesis. Here, we report that the transcription factor Sp7 plays an essential role in osteocytogenesis. Severe defects in bone integrity and osteocyte dendrite morphology are noted in mice lacking Sp7 at the stage of the osteoblast-to-osteocyte transition. In osteocytes, Sp7 controls expression of a neuronally-enriched gene network. Analysis of the osteocyte-specific Sp7 cistrome reveals distinct genomic binding motifs and target sites distinct from those in osteoblasts. Amongst osteocyte-specific Sp7 targets, the secreted peptide osteocrin rescues Sp7-deficient defects. Single-cell transcriptional profiling of cells undergoing osteocytogenesis identifies novel Sp7-dependent transitional cell types enriched in genes linked to human fracture risk. Finally, humans with an SP7 R316C mutation display osteocyte morphology defects similar to those observed in mouse models. These findings demonstrate that cuboidal osteoblasts use a neuronally-enriched Sp7/osteocrin gene expression program to differentiate into dendrite-bearing osteocytes.
2021-09-20 | GSE154716 | GEO
Project description:Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin
| PRJNA647296 | ENA
Project description:Osteocytes are long-lived, highly interconnected, terminally differentiated osteoblasts which reside within mineralized bone matrix. They constitute about 95% of adult bone cells and play important functions in the regulation of bone remodeling, phosphate homeostasis, and mechanical stimuli sensing and response. However, the role of osteocytes in the pathogenesis of congenital diseases of bone such as osteogenesis imperfecta (OI) is poorly understood. This study characterized in vivo transcriptional changes in osteocytes from the CrtapKO and oim/oim mouse models of OI, using RNA-sequencing on osteocyte-enriched cortical bone from femur and tibia. These models were chosen because they mimic two types of OI with different genetic mutations which result in distinct type I collagen defects. Hundreds of transcripts were dysregulated in either model of OI compared to WT, but 281 of these were similarly up- or down-regulated in both. Conversely, very few transcripts were differentially expressed between the CrtapKO and oim/oim mice, indicating that distinct alterations in type I collagen can lead to shared pathogenic processes and similar phenotypic outcomes. Bioinformatics analyses identified several critical hubs of dysregulation that were enriched in annotation terms such as development and differentiation, ECM and collagen fibril organization, cell adhesion, signaling, regulatory processes, pattern binding, chemotaxis, and cell projections. The data further indicated alterations in important signaling pathways such as WNT and TGF-β. Overall, our study suggested that the osteocyte transcriptome is broadly dysregulated in OI, that transcriptomic alterations in OI can be strikingly similar despite arising from different genetic mutations, and that the potential consequences of osteocyte dysregulation deserve further investigation.
2020-07-21 | GSE154748 | GEO
Project description:The osteocyte transcriptome is extensively dysregulated in mouse models of Osteogenesis Imperfecta
| PRJNA647367 | ENA
Project description:Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin [scRNA-Seq]
| PRJNA647304 | ENA
Project description:Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin [ChIP-Seq]
| PRJNA647303 | ENA
Project description:Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin [RNA-Seq]
| PRJNA647302 | ENA