Rattus norvegicus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA131101 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Osteosarcomas typically arise from the metaphyseal cells of juvenile long bones, in contrast to most cancers that develop in aged individuals. Here, we show that the cyclin-dependent kinase inhibitor p21 is expressed in proliferating osteoblasts within the juvenile metaphysis in response to replication stress. Single-cell RNA sequencing focused on the juvenile metaphysis reveals a hierarchical differentiation trajectory of osteoblast-lineage cells, with active proliferation and DNA damage responses predominantly occurring in immature osteoblasts. We find that proliferation of p21+ osteoblasts is mediated by Hedgehog signaling associated with Indian hedgehog (IHH) expression in the growth plate. Consistently, the number of p21+ osteoblasts is markedly reduced following growth plate maturation or pharmacological inhibition of Hedgehog signaling. Induction of c-Myc—a known driver of replication stress and frequently amplified in early-stage osteosarcoma—enhances osteoblast proliferation specifically in juvenile mice, while concurrently augmenting replication stress responses including p53 activation. This c-Myc-driven proliferation remains dependent on Hedgehog signaling and is not sustained after growth plate maturation. Remarkably, functional inactivation of p53 enables continuous proliferation of c-Myc-induced osteoblasts, independent of IHH expression at the growth plate, leading to rapid and widespread metastasis to the lungs. These findings suggest that intrinsic DNA damage responses to replication stress, together with the spatiotemporal restriction of mitogen signaling, safeguard against oncogenic transformation in osteoblasts. Collectively, we uncover the unappreciated aspects of juvenile metaphyseal tissue homeostasis in mice, which may account for the characteristic age of onset, anatomical specificity, and mutational profile of human osteosarcomas.
2026-06-05 | GSE297558 | GEO
Project description:Osteosarcomas typically arise from the metaphyseal cells of juvenile long bones, in contrast to most cancers that develop in aged individuals. Here, we show that the cyclin-dependent kinase inhibitor p21 is expressed in proliferating osteoblasts within the juvenile metaphysis in response to replication stress. Single-cell RNA sequencing focused on the juvenile metaphysis reveals a hierarchical differentiation trajectory of osteoblast-lineage cells, with active proliferation and DNA damage responses predominantly occurring in immature osteoblasts. We find that proliferation of p21+ osteoblasts is mediated by Hedgehog signaling associated with Indian hedgehog (IHH) expression in the growth plate. Consistently, the number of p21+ osteoblasts is markedly reduced following growth plate maturation or pharmacological inhibition of Hedgehog signaling. Induction of c-Myc—a known driver of replication stress and frequently amplified in early-stage osteosarcoma—enhances osteoblast proliferation specifically in juvenile mice, while concurrently augmenting replication stress responses including p53 activation. This c-Myc-driven proliferation remains dependent on Hedgehog signaling and is not sustained after growth plate maturation. Remarkably, functional inactivation of p53 enables continuous proliferation of c-Myc-induced osteoblasts, independent of IHH expression at the growth plate, leading to rapid and widespread metastasis to the lungs. These findings suggest that intrinsic DNA damage responses to replication stress, together with the spatiotemporal restriction of mitogen signaling, safeguard against oncogenic transformation in osteoblasts. Collectively, we uncover the unappreciated aspects of juvenile metaphyseal tissue homeostasis in mice, which may account for the characteristic age of onset, anatomical specificity, and mutational profile of human osteosarcomas.
2026-06-05 | GSE333438 | GEO
Project description:Osteosarcomas typically arise from the metaphyseal cells of juvenile long bones, in contrast to most cancers that develop in aged individuals. Here, we show that the cyclin-dependent kinase inhibitor p21 is expressed in proliferating osteoblasts within the juvenile metaphysis in response to replication stress. Single-cell RNA sequencing focused on the juvenile metaphysis reveals a hierarchical differentiation trajectory of osteoblast-lineage cells, with active proliferation and DNA damage responses predominantly occurring in immature osteoblasts. We find that proliferation of p21+ osteoblasts is mediated by Hedgehog signaling associated with Indian hedgehog (IHH) expression in the growth plate. Consistently, the number of p21+ osteoblasts is markedly reduced following growth plate maturation or pharmacological inhibition of Hedgehog signaling. Induction of c-Myc—a known driver of replication stress and frequently amplified in early-stage osteosarcoma—enhances osteoblast proliferation specifically in juvenile mice, while concurrently augmenting replication stress responses including p53 activation. This c-Myc-driven proliferation remains dependent on Hedgehog signaling and is not sustained after growth plate maturation. Remarkably, functional inactivation of p53 enables continuous proliferation of c-Myc-induced osteoblasts, independent of IHH expression at the growth plate, leading to rapid and widespread metastasis to the lungs. These findings suggest that intrinsic DNA damage responses to replication stress, together with the spatiotemporal restriction of mitogen signaling, safeguard against oncogenic transformation in osteoblasts. Collectively, we uncover the unappreciated aspects of juvenile metaphyseal tissue homeostasis in mice, which may account for the characteristic age of onset, anatomical specificity, and mutational profile of human osteosarcomas.
2026-06-05 | GSE297564 | GEO
Project description:Microarray analysis of perichondral and reserve growth plate zones
| PRJNA103349 | ENA
Project description:Spatial and Temporal Regulation of Gene Expression in the Mammalian Growth Plate
| PRJNA117283 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2015-01-01 | GSE58692 | GEO
Project description: Not available
| S-EPMC7161169 | biostudies-literature
Project description:Expression data of articular and growth plate cartilage zones in 10-day-old rat proximal tibial epiphysis
| PRJNA235949 | ENA
Project description: Not available
| BMID000000140404 | biostudies-other
Project description:Knee osteoarthritis (KOA), as a degenerative multifactorial disease, affects the quality of life and mental health of patients, and also brings a huge socioeconomic burden. Treating synovitis have shown promise as anti-inflammatory therapeutics in mitigating OA symptoms and disease progression. Here, by analysing synovial single-cell sequencing (scRNA-seq) data from KOA, we found that synovial fibroblasts (FLS) in OA synovium showed a distinct pro-inflammatory phenotype. We collected synovial tissue from patients with clinical OA as well as from healthy donors, and histological examination was consistent with findings in scRNA-seq. Inspired by recent cross-tissue fibroblast lineage studies, we identified by sequencing that healthy FLS in synovial tissues share transcriptome-level similarities with dermal fibroblasts (DFb). Subsequently, we revealed the local as well as systemic distribution of intra-articular injected DFbs by constructing/extracting two types of rat fibroblasts (luciferase DFbs as well as GFP DFbs). The results demonstrate that DFbs can be locally retained in the synovium for up to three weeks following targeted engrafting on it. And intra-articular injection does not result in DFbs migration to vital organs or the occurrence of histological changes in these organs. A rat model of KOA was constructed by anterior cruciate ligament transection (ACLT) in order to study the therapeutic effect of DFbs on KOA. After injection, the rats showed improvement in painful gait. In addition, histological as well as imaging results showed reduced synovitis and improvement in articular cartilage. Finally we verified the protective effect of DFbs on cytokine-stimulated chondrocytes in a co-culture system.
2026-06-24 | GSE304724 | GEO