Time- and cell-specific activation of BMP signaling restrains chondrocyte hypertrophy
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ABSTRACT:
PROVIDER: PRJNA1013808 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25939143.fastq.gz | Fastqsanger.gz | |||
| SRR25939144.fastq.gz | Fastqsanger.gz | |||
| SRR25939145.fastq.gz | Fastqsanger.gz | |||
| SRR25939146.fastq.gz | Fastqsanger.gz | |||
| SRR25939147.fastq.gz | Fastqsanger.gz |
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Project description:Differentiated chondrocytes from populations of human bone marrow stromal cells including skeletal stem cells (hBMSCs/SSCs) and induced pluripotent stem cells (hiPSCs) have the potential to restore damaged cartilage, yet chondrocyte hypertrophy is a barrier for translational therapy. However, hBMSCs/SSCs attached to a hyaluronic acid-coated fibrin microbead scaffold (HyA-FMBs) produce cartilage that resists hypertrophy. We show that HyA-FMBs initially suppress Bone Morphogenic Protein (BMP) signaling early in chondrogenic differentiation of hBMSCs/SSCs, then restore BMP signaling in a stable chondrogenic population enriched for Insulin-like Growth Factor Binding Protein 5 and Matrix Gla Protein. We subsequently developed a serumfree hiPSC differentiation strategy that inhibited, then activated BMP signaling in a purified subpopulation derived from ?chondrospheroids? that exhibited stable expression of Type II Collagen, Aggrecan (ACAN), and Lubricin (PRG4) and minimal e xpression of Type X Collagen. Overall, timed, and selective BMP signaling restrains chondrocyte hypertrophy, supporting the potential of chondrospheroid-derived cells for clinical utility in osteoarthritis.
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Project description:Smad4 is a central mediator of canonical TGF/BMP signaling and plays important roles in mesenchymal cell aggregation, chondrocyte differentiation, osteoblast differentiation and maturation. However, the regulatory mechanism of Smad4 underlying chondrocyte hypertrophy during skeletal development is unknown. To elucidate the molecular mechanism by which Smad4 deficiency impairs chondrocyte hypertrophy, we performed high-throughput RNA-seq to identify target genes involved in Smad4-regulated chondrocyte hypertrophy. Our results suggest that Smad4 controls chondrocyte hypertrophy through regulating Runx2 expression during skeletal development.
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Project description:Smad4 is a central mediator of canonical TGF/BMP signaling and plays important roles in mesenchymal cell aggregation, chondrocyte differentiation, osteoblast differentiation and maturation. However, the regulatory mechanism of Smad4 underlying chondrocyte hypertrophy during skeletal development is unknown. To elucidate the molecular mechanism by which Smad4 deficiency impairs chondrocyte hypertrophy, we performed high-throughput Chip-seq to identify target genes involved in Smad4-regulated chondrocyte hypertrophy. Our results suggest that Smad4 controls chondrocyte hypertrophy through regulating Runx2 expression during skeletal development.
2018-05-07 | GSE114081 | GEO
Project description:A comprehensive analysis of Sox9 binding profiles in developing chondrocytes identified marked enrichment of an AP-1-like motif (Ohba et al. 2015). Here, we have explored the functional interplay between Sox9 and AP-1 in mammalian chondrocyte development. Among AP-1 family members, Jun and Fosl2 were highly expressed within prehypertrophic and early hypertrophic chondrocytes. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) showed a striking overlap in Jun- and Sox9-bound regions throughout the chondrocyte genome, a reflection of direct binding of each factor to target motifs in shared enhancers, and physical interactions of AP-1 with Sox9. In vitro expression analysis indicates that direct co-binding of Sox9 and AP-1 at target motifs enhanced target gene expression, while protein-protein interactions suppressed AP-1- and Sox9-driven transcription. Analysis of prehypertrophic chondrocyte removal of Sox9 demonstrated Sox9 was essential for hypertrophic chondrocyte development, while in vitro and ex vivo analyses showed AP-1 promotes chondrocyte hypertrophy. Sox9 and Jun co-bound and co-activated a Col10a1 enhancer in Sox9 and AP-1 motif-dependent manners consistent with their combined action promoting hypertrophic gene expression. Together, the data support a model where AP-1-family members promote Sox9-action in the transition of chondrocytes to a terminal hypertrophic program. Intersection of ChIP-seq data from Sox9 and AP-1 factor Jun, RNA-seq data from developing rib chondrocytes and Col10a1mCherry positive hypertrophic chondrocytes in neonatal mice to uncover regulation of Sox9 by AP-1 factors during chondrocyte hypertrophy.
2016-02-29 | E-GEOD-73372 | biostudies-arrayexpress
Project description:A comprehensive analysis of Sox9 binding profiles in developing chondrocytes identified marked enrichment of an AP-1-like motif (Ohba et al. 2015). Here, we have explored the functional interplay between Sox9 and AP-1 in mammalian chondrocyte development. Among AP-1 family members, Jun and Fosl2 were highly expressed within prehypertrophic and early hypertrophic chondrocytes. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) showed a striking overlap in Jun- and Sox9-bound regions throughout the chondrocyte genome, a reflection of direct binding of each factor to target motifs in shared enhancers, and physical interactions of AP-1 with Sox9. In vitro expression analysis indicates that direct co-binding of Sox9 and AP-1 at target motifs enhanced target gene expression, while protein-protein interactions suppressed AP-1- and Sox9-driven transcription. Analysis of prehypertrophic chondrocyte removal of Sox9 demonstrated Sox9 was essential for hypertrophic chondrocyte development, while in vitro and ex vivo analyses showed AP-1 promotes chondrocyte hypertrophy. Sox9 and Jun co-bound and co-activated a Col10a1 enhancer in Sox9 and AP-1 motif-dependent manners consistent with their combined action promoting hypertrophic gene expression. Together, the data support a model where AP-1-family members promote Sox9-action in the transition of chondrocytes to a terminal hypertrophic program.
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Project description:In order to better understand the mechanisms of chondrocyte hypertrophy, we induced hypertrophic chondrocytes from 414C2 iPSCs and analyzed their gene expression profile. This dataset includes the expression data obtained from iPSC-derived sclerotome and cartilage on days -1, 28, and 56 of induction. Day 56 samples were compared to day 28 samples to analyze pathways involved in chondrocyte hypertrophy.
2021-02-24 | GSE157955 | GEO
Project description:Smad4 deficiency impairs chondrocyte hypertrophy via the Runx2 transcription factor in mouse skeletal development
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Project description:Objective: When primary chondrocytes are cultured in monolayer, they undergo dedifferentiation during which they lose their phenotype and their capacity to form cartilage. Dedifferentiation is an obstacle for cell therapy for cartilage degeneration. In this study, we aimed to systemically evaluate the changes in gene expression during dedifferentiation of human articular chondrocytes to identify underlying mechanisms. Methods: RNA was isolated from monolayer-cultured primary human articular chondrocytes at serial passages. Gene expression was analyzed by microarray. Based on the microarray analysis, relevant genes and pathways were identified. Their functions in chondrocyte dedifferentiation were further investigated in detail. Results: In vitro expanded human chondrocytes showed progressive changes in gene expression during dedifferentiation. Strikingly, an overall decrease in total gene expression was detected. Genes in the Wnt and BMP pathways exhibited significant changes in expression. The non-canonical rather than the canonical Wnt pathway was found to be involved in the loss of collagen II synthesis. BMP2 was able to decelerate the dedifferentiation and reinforce the maintenance of chondrocyte phenotype in monolayer culture. DNA methylation was in part responsible for the expression downregulation of a set of genes. Conclusion: Our study revealed the roles of ERK, Wnt and BMP pathways as well as DNA methylation in chondrocyte dedifferentiation in monolayer culture. RNA human chondrocytes were allowed to dedifferentiate for 8 passages. RNA was isolated at week 0, 2 ,4, 6 and 8, which was subjected to whole genome gene expression analysis.
2012-11-14 | E-GEOD-42235 | biostudies-arrayexpress
Project description:Cell cycle regulation is critical for chondrocyte differentiation and hypertrophy. Recently we identified the Notch signaling pathway as an important regulator of chondrocyte proliferation and differentiation during mouse cartilage development. To investigate the underlying mechanisms, we assessed the role for Notch signaling regulation of the cell cycle during chondrocyte differentiation. Real-time RT-PCR data showed that over-expression of the Notch Intracellular Domain (NICD) significantly induced the expression of p57, a cell cycle inhibitor, in chondrocytes. Flow cytometric analyses further confirmed that over-expression of NICD in chondrocytes enhances the G0/G1 cell cycle transition and cell cycle arrest. In contrast, treatment of chondrocytes with the Notch inhibitor, DAPT, decreased both endogenous and BMP2-induced SMAD 1/5/8 phosphorylation and knockdown of SMAD 1/5/8 impaired NICD-induced chondrocyte differentiation and p57 expression. Co-immunoprecipitation using p-SMAD 1/5/8 and NICD antibodies further showed a strong interaction of these proteins during chondrocyte maturation. Finally, RT-PCR and Western blot results revealed a significant reduction in the expression of the SMAD-related phosphatase, PPM1A, following NICD over-expression. Taken together, our results demonstrate that Notch signaling induces cell cycle arrest and thereby initiates chondrocyte hypertrophy via BMP/SMAD-mediated up-regulation of p57.
| S-EPMC4857138 | biostudies-literature
Project description:In Drosophila, efferent neurons gain access to a target-derived BMP signal in the periphery that is required for differentiation and/or synaptic growth and neurotransmission. This requires transcriptional activity of the BMP-activated Smad transcription factors, but the Smad-bound enhancers and BMP-regulated effector genes they control remain unidentified. In the absence of insight into how BMP signaling controls these fundamental aspects of neuronal development and function, here we test whether Smads act directly at widely-deployed archetypal Smad-binding motifs to directly co-regulate batteries of BMP-responsive genes. To target these motifs for analysis, we employed a bioinformatics approach to identify candidate motifs conforming to the consensus 15bp BMP-Activation Element (BMP-AE). After filtering for high conservation and proximity to neuronally-expressed genes, we prioritized 62 BMP-AEs for analysis. Testing the in vivo enhancer activity of 58 genomic fragments containing these BMP-AEs in transgenic reporters, we show that 61% are functional BMP enhancers in diverse motoneuron and neuropeptidergic neuronal populations, and that the BMP-AE motif itself is required for activity. Moreover, 60% of these functional BMP-AEs were located within 20kb of at least one BMP activated gene, as identified by RNAseq analysis. Finally, we show that the BMP-AE motif plays a conserved activator function in the vertebrate nervous system, by electroporation in the developing chick neural tube. Our results provide evidence that BMP signaling controls neuronal development and function by directly coordinating networks of genes through widespread deployment of conserved, consensus Smad-binding motifs.
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