Molecular Profiling of Failed Endochondral Ossification in Mucopolysaccharidosis VII
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ABSTRACT:
PROVIDER: PRJNA533818 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8932790_1.fastq.gz | Fastqsanger.gz | |||
| SRR8932790_2.fastq.gz | Fastqsanger.gz | |||
| SRR8932800_1.fastq.gz | Fastqsanger.gz | |||
| SRR8932800_2.fastq.gz | Fastqsanger.gz | |||
| SRR8932791_1.fastq.gz | Fastqsanger.gz |
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Project description:Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient activity of β-glucuronidase, leading to progressive accumulation of incompletely degraded heparan, dermatan and chondroitin sulfate glycosaminoglycans (GAGs). Patients with MPS VII exhibit progressive skeletal deformity including kyphoscoliosis and joint dysplasia, which decrease quality of life and increase mortality. Previously, using the naturally-occurring canine model, we demonstrated that one of the earliest skeletal abnormalities to manifest in MPS VII is failed initiation of secondary ossification in vertebrae and long bones at the requisite postnatal developmental stage. The objective of this study was to obtain global insights into the molecular mechanisms underlying this failed initiation of secondary ossification using whole transcriptome sequencing (RNA-Seq). Epiphyseal tissue was isolated from the vertebrae of control and MPS VII affected dogs at 9 and 14 days-of-age (n=5 for each group). Differences in global gene expression across this developmental window for both cohorts were established using RNA-Seq. A targeted analysis focused on signaling pathways important in the regulation of endochondral ossification, and a subset of gene expression changes were validated using qPCR. Principal Component Analysis revealed clustering of samples from each group, indicating clear effects of both age and disease state. At 9 days-of-age, 1375 genes were significantly differentially expression between MPS VII and control, and by 14 days-of-age, this increased to 4719 genes. Osteoactivin (GPNMB) was the top upregulated gene in MPS VII at both ages. Targeted analysis revealed temporal changes in gene expression from 9 to 14 days-of-age in control samples consistent with chondrocyte maturation, cartilage resorption, and osteogenesis. In MPS VII samples, however, elements of key osteogenic pathways such as Wnt/β-catenin and BMP signaling were dysregulated. In conclusion, this study represents the first step towards identifying druggable therapeutic targets and putative biomarkers for bone disease in MPS VII patients during postnatal growth.
2020-07-01 | GSE130088 | GEO
Project description:Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient activity of β-glucuronidase, leading to progressive accumulation of incompletely degraded heparan, dermatan, and chondroitin sulfate glycosaminoglycans (GAGs). Patients with MPS VII exhibit progressive skeletal deformity including kyphoscoliosis and joint dysplasia, which decrease quality of life and increase mortality. Previously, using the naturally-occurring canine model, we demonstrated that one of the earliest skeletal abnormalities to manifest in MPS VII is failed initiation of secondary ossification in vertebrae and long bones at the requisite postnatal developmental stage. The objective of this study was to obtain global insights into the molecular mechanisms underlying this failed initiation of secondary ossification. Epiphyseal tissue was isolated postmortem from the vertebrae of control and MPS VII-affected dogs at 9 and 14 days-of-age (n = 5 for each group). Differences in global gene expression across this developmental window for both cohorts were measured using whole-transcriptome sequencing (RNA-Seq). Principal Component Analysis revealed clustering of samples within each group, indicating clear effects of both age and disease state. At 9 days-of-age, 1375 genes were significantly differentially expressed between MPS VII and control, and by 14 days-of-age, this increased to 4719 genes. A targeted analysis focused on signaling pathways important in the regulation of endochondral ossification was performed, and a subset of gene expression differences were validated using qPCR. Osteoactivin (GPNMB) was the top upregulated gene in MPS VII at both ages. In control samples, temporal changes in gene expression from 9 to 14 days-of-age were consistent with chondrocyte maturation, cartilage resorption, and osteogenesis. In MPS VII samples, however, elements of key osteogenic pathways such as Wnt/β-catenin and BMP signaling were not upregulated during this same developmental window suggesting that important bone formation pathways are not activated. In conclusion, this study represents an important step towards identifying therapeutic targets and biomarkers for bone disease in MPS VII patients during postnatal growth.
| S-EPMC6813906 | biostudies-literature
Project description:Mesenchymal cell-derived septoclasts resorb cartilage during endochondral ossification and fracture healing
2021-12-11 | GSE154076 | GEO
Project description:Appendicular growth and bone mass acquisition are controlled by a variety of growth factors, hormones, and mechanical forces in a dynamic process called endochondral ossification. Chondrocytes in the growth plate must proliferate and undergo hypertrophy to drive growth plate expansion and lay the template for bone. Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 and 2 (Phlpp1 and Phlpp2) are protein phosphatases that regulate intracellular signaling cascades through posttranslational modification of AKT, PKC, and S6K, among others. Phlpp1 controls chondrocyte proliferation and survival and germline deletion of Phlpp1 suppresses bone lengthening. Here, we demonstrate that Phlpp2 does not regulate endochondral ossification. Phlpp2-/- mice are phenotypically indistinguishable from their wildtype (WT) littermates, with similar bone length, bone mass, and growth plate dynamics. By contrast, Phlpp1/2-/- mice are phenotypically indistinguishable from Phlpp1-/- mice. Deletion of Phlpp1 or Phlpp2 had moderate effects on the chondrocyte transcriptome and proteome compared to WT control cells. By contrast, Phlpp1-/- and Phlpp1/2-/- chondrocytes had significantly altered phospho-proteomes compared to WT and Phlpp2-/- chondrocytes. Data integration via multiomics analysis revealed that RAF-MEK-ERK signaling was altered in cells lacking Phlpp1. In conclusion, these data demonstrate that Phlpp1, but not Phlpp2, regulates endochondral ossification via the chondrocyte phospho-proteome.
2024-09-30 | GSE265773 | GEO
Project description:Endochondral ossification forms and grows the majority of the mammalian skeleton and is tightly controlled through gene regulatory networks. The forkhead box transcription factors Foxc1 and Foxc2 have been demonstrated to regulate aspects of osteoblast function in the formation of the skeleton but their roles in chondrocytes to control endochondral ossification are less clear. We demonstrate that Foxc1 expression is directly regulated by SOX9 activity, one of the earliest transcription factors to specify the chondrocyte lineages. Moreover we demonstrate that elevelated expression of Foxc1 promotes chondrocyte differentiation in mouse embryonic stem cells and loss of Foxc1 function inhibits chondrogenesis in vitro. Using chondrocyte-targeted deletion of Foxc1 and Foxc2 in mice, we reveal a role for these factors in chondrocyte differentiation in vivo. Loss of both Foxc1 and Foxc2 caused a general skeletal dysplasia predominantly affecting the vertebral column. The long bones of the limb were smaller and mineralization was reduced and organization of the growth plate was disrupted. In particular, the stacked columnar organization of the proliferative chondrocyte layer was reduced in size and cell proliferation in growth plate chondrocytes was reduced. Differential gene expression analysis indicated disrupted expression patterns in chondrogenesis and ossification genes throughout the entire process of endochondral ossification in Col2-cre;Foxc1Δ/Δ;Foxc2Δ/Δ embryos. Our results suggest that Foxc1 and Foxc2 are required for correct chondrocyte differentiation and function. Loss of both genes results in disorganization of the growth plate, reduced chondrocyte proliferation and delays in chondrocyte hypertrophy that prevents correct ossification of the endochondral skeleton.
2021-09-08 | GSE165951 | GEO
Project description:Endochondral ossification (EO) is the natural route for the regeneration of large and mechanically challenged bone defects. Regeneration occurs via a fibrocartilagenous phase which turns into bone upon vascularization and the formation of a transient collagen type X extra cellular matrix. These two critical initiator of EO are mediated by Hedgehog proteins. We investigated a tissue engineering approach using Sonic Hedgehog (Shh) as a pleiotropic factor regulating the in vitro formation of a vascularized bone tissue precursor for in vivo endochondral bone formation. The tissue engineered graft was formed using human mesenchymal stem cells and prevascularized using human umbilical vein endothelial cells. We show that Shh induced, in vitro, the maturation of the engineered vascular network along with the expression of collagen type X which resulted, in vivo, in an improved vascularization and the rapid formation of large amounts of osteoids through EO. Osteoids further matured into, currently unmatched, clinically relevant amount of lamellar bone including osteoclasts, bone lining cells and bone marrow-like cavities. This result suggests that Hh is a master regulator of EO allowing for the formation of complex tissues with considerable therapeutic potential for bone regeneration. The effect of Cyclopamine on expression of Hedgehog, angiogenesis and axon guidance marker genes was analyzed by seeding a coculture of 92% hMSCs and 8% huvEC supplemented or not in cyclopamine, for 12 days
2012-09-01 | E-GEOD-22293 | biostudies-arrayexpress
Project description:Antler primary growth center is located in the distal tip of growing antler with five consecutive tissue layers under the velvet skin. Because of blastema progenitor cells of outmost reserve mesenchymal layer with multipotent differentiation capacity, antler regeneration recapitulates embryonic skeletal development through endochondral os-sification process. To further decipher this modified endochondral ossification, we profile deer antler proteome atlas with 8000 proteins, covering the whole five layers that comprehensively represent the mesenchymal condensation, rapid mesenchymal proliferation, chondrocyte hypertrophy, cartilage mineralization. By integrating three clustering methods including WGCNA, Fuzzy C-means clustering, and Monotonic feature selector, we elucidate proteome dynamics within the growth center, identifying key factors and elucidating biological processes through GO enrichment analysis. Through comparative analysis of RNA-seq and Proteomic studies, our results reveal that mRNA exhibits greater fluctuations during the endochondral ossification process. This research offers a valuable model for investigating hub genes and their biological function involved in organ regeneration.
2025-07-21 | PXD066352 |
Project description:In China, the incidence of fracture non-unions is relatively high. Impaired endochondral ossification may lead to nonunion due to improper mechanical loading. As a mechanosensitive ion channel protein, Piezo1mediates mechanical transduction and induces calcium inward flow. Our early study showed that the osteogenic and angiogenic capacity of chondrocytes was reduced, if Piezo1 gene was knocked out on chondrocytes. Moreover, the expression of mitochondrion translation related gene LARS2 was signaling increased. Therefore, we hypothesize that the mechanical loading may cause endochondral ossification through the Piezo1- LARS2 signaling pathway. We will use conditioned gene knockout mice and Peizo1 knockdown stable cell line to support the hypothesis. Our goals include investigating the changes of Piezo1 expression during endochondral ossification of femoral fracture healing in mice under mechanical loading; investigating the response of Piezo1 channels on chondrocytes to mechanical stimulation and its role and mechanism in regulating chondrocyte osteogenesis and angiogenesis, maintaining the normal mitochondrial function in vitro; analysing the key molecular and signal network downstream of Piezo1 through the multi-omics techniques; and exploring the response mechanism of Piezo1 under vibrating stimulus. This project aims to study the molecular mechanism of Piezo1-mediated force-biological information transition and its role in endochondral ossification. We hope it provides an effective intervention target for preventing and treating fracture nonunion.
2024-12-19 | GSE242712 | GEO
Project description:We used microarray to detect pathway differences in the hippocampus in mucopolysaccharidosis type VII ( MPS VII ), a mouse model of a lysosomal storage disease Pathway changes were similar to those found in different strain where MPS VII mutation was backcrossed on a C3h-heouj background and implicated immune, vesicle and other pathways
2015-12-23 | GSE76283 | GEO
Project description:Phlpp1 regulates endochondral ossification via the chondrocyte phospho-proteome
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