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DNA methylation mediated Rbpjksuppression protects against fracture nonunion caused by systemic inflammation

ABSTRACT: DNA methylation mediated Rbpjksuppression protects against fracture nonunion caused by systemic inflammation

PROVIDER: PRJNA1015124 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26001189_1.fastq.gz	Fastqsanger.gz
	SRR26001189_2.fastq.gz	Fastqsanger.gz
	SRR26001190_1.fastq.gz	Fastqsanger.gz
	SRR26001190_2.fastq.gz	Fastqsanger.gz
	SRR26001191_1.fastq.gz	Fastqsanger.gz

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DNA methylation mediated Rbpjksuppression protects against fracture nonunion caused by systemic inflammation

Project description:Challenging skeletal repairs are frequently seen in patients experiencing systemic inflammation. Current therapies aimed at mitigating inflammation or enhancing stem cell function with osteogenic factors yield inconsistent clinical outcomes. To tackle the complexity and heterogeneity of fracture repair process, we performed single-cell RNA sequencing and revealed that progenitor cell was one of the major lineages responsive to elevated inflammation and this response adversely affected progenitor differentiation by upregulation ofRbpjkin fracture nonunion.We then validated the interplay between inflammation (via Ikk2ca) and Rbpjkspecifically in progenitors by using genetic animal models. Focusing on epigenetic regulation, we identifiedRbpjkas a direct target of Dnmt3b. Mechanistically, intrinsic inflammation decreased Dnmt3b expression in progenitor cells, consequently leading toRbpjkupregulation via hypomethylation within its promoter region. We also showed thatDnmt3bloss-of-function mice phenotypically recapitulated the fracture repair defects observed inIkk2camice, whereasDnmt3btransgenic mice alleviated fracture repair defects induced byIkk2ca. Moreover,Rbpjkablation restored fracture repair in bothIkk2camice andDnmt3bloss-of-function mice. Altogether, this work elucidates a common mechanism involving NF-kB/Dnmt3b/Rbpjkaxis within the context of inflamed bone regeneration. Building upon this novel mechanistic insight, we applied local treatment with epigenetically modified progenitor cells in RA mice and showed a functional restoration of bone regeneration under inflammatory condition through an increase in progenitor differentiation potential. These findings underscore the promise of epigenetic-based therapeutic interventions for addressing delayed fracture union and nonunion particularly associated with systemic inflammation.

2024-10-22 | GSE242836 | GEO

miRNA expression data from callus in standard fracture healing models and from fibrous tissues in nonunion models in rats on post-fracture day 14

Project description:Profiling of miRNA expressions comparing standard fracture healing models with nonunion models in rats 12w, male, Sprague–Dawley rats were used in this study. Animals were randomized to receive either a surgical treatment that has been shown to produce a nonunion or to a standard stabilized closed femoral shaft fracture that is known to successfully heal. The details of these procedures have been previously described. Briefly, to produce standard healing models, a 1.2-mm diameter K-wire was inserted retrograde into the right femoral intramedullary canal and a closed transverse femoral shaft fracture was produced using a three-point bending apparatus with a drop weight . To produce the nonunion, the fractured site was additionally exposed, and the periosteum was cauterized circumferentially for a distance of 2 mm on each side of the fracture . Five animals from each group were euthanized on post-fracture day 14 for microarray analysis.

2015-09-03 | E-GEOD-55088 | biostudies-arrayexpress

miRNA expression data from callus in standard fracture healing models and from fibrous tissues in nonunion models in rats on post-fracture day 14

Project description:Profiling of miRNA expressions comparing standard fracture healing models with nonunion models in rats

2015-09-03 | GSE55088 | GEO

DNA methylation-mediated Rbpjk suppression protects against fracture nonunion caused by systemic inflammation.

Project description:Challenging skeletal repairs are frequently seen in patients experiencing systemic inflammation. To tackle the complexity and heterogeneity of the skeletal repair process, we performed single-cell RNA sequencing and revealed that progenitor cells were one of the major lineages responsive to elevated inflammation and this response adversely affected progenitor differentiation by upregulation of Rbpjk in fracture nonunion. We then validated the interplay between inflammation (via constitutive activation of Ikk2, Ikk2ca) and Rbpjk specifically in progenitors by using genetic animal models. Focusing on epigenetic regulation, we identified Rbpjk as a direct target of Dnmt3b. Mechanistically, inflammation decreased Dnmt3b expression in progenitor cells, consequently leading to Rbpjk upregulation via hypomethylation within its promoter region. We also showed that Dnmt3b loss-of-function mice phenotypically recapitulated the fracture repair defects observed in Ikk2ca-transgenic mice, whereas Dnmt3b-transgenic mice alleviated fracture repair defects induced by Ikk2ca. Moreover, Rbpjk ablation restored fracture repair in both Ikk2ca mice and Dnmt3b loss-of-function mice. Altogether, this work elucidates a common mechanism involving a NF-κB/Dnmt3b/Rbpjk axis within the context of inflamed bone regeneration. Building on this mechanistic insight, we applied local treatment with epigenetically modified progenitor cells in a previously established mouse model of inflammation-mediated fracture nonunion and showed a functional restoration of bone regeneration under inflammatory conditions through an increase in progenitor differentiation potential.

| S-EPMC10849763 | biostudies-literature

A Transcriptional Hub for Endochondral ossification adn Fracture Repair.

Project description:After injury, bone tissue initiates a reparative response that will recover its structure and function, failure to initiate or delay this response results in fracture nonunion. The molecular mechanisms underlying fracture nonunion appearance are not yet stablished. We proposed that the signaling pathways derived from hypoxia and mediated by reactive oxygen species (ROS) homeostasis control Bmp2 expression and fracture healing initiation, having potential to induce fracture nonunion when excessive ROS develops into oxidative stress. Here, we silenced Apex1, the final transducer of ROS signaling and responsible of the activation of key transcription factors by oxidoreduction of cysteines, evaluating its role during endochondral ossification and fracture repair. Silencing Apex1 in limb bud mesenchyme results in transient metaphyseal dysplasia derived of impaired chondrocyte differentiation. During bone regeneration, silencing Apex1 generates a fracture nonunion phenotype characterized by delayed fracture healing initiation with impaired periosteal response and reduced chondrocyte and osteoblasts differentiation. In addition, compromised chondrocyte differentiation hampers fracture healing progression and callus vascularization. Our data supports a molecular mechanism of fracture healing initiation dependent of hypoxia derived ROS signaling in mesenchymal progenitors.

2025-11-24 | GSE278433 | GEO

809094 Biomarker Identification in Fracture Healing (experiment #5150 Feb 2015)

Project description:The specific genes that distinguish normal fracture healing from abnormal healing or nonunion in humans are unknown. This study was an exploratory investigation of peripheral blood from acutely injured fracture patients collected over multiple days to compare normal healers, slow healers, and nonunion outcomes. We used microarrays to do a global comparison between acutely injured (AI) subjects (AIS) vs age and sex matched healthy volunteers (HV) and chronic Nonunion (NU) patients.

2017-01-06 | GSE93217 | GEO

809094 Biomarker Identification in Fracture Healing (experiment #5149 Feb 2015)

2017-01-06 | GSE93216 | GEO

809094 Biomarker Identification in Fracture Healing (experiment #5201-5202 Jun 2015)

Project description:The specific genes that distinguish normal fracture healing from abnormal healing or nonunion in humans are unknown. This study was an exploratory investigation of peripheral blood from acutely injured fracture patients collected over multiple days to compare normal healers, slow healers, and nonunion outcomes. We used microarrays to do a global comparison between acutely injured (AI) subjects (AIS) vs. age- and sex-matched healthy volunteers (HV) and chronic Nonunion (NU) patients.

2017-01-11 | GSE93387 | GEO

809094 Biomarker Identification in Fracture Healing (experiment #5200-5203 Jun 2015)

Project description:The specific genes that distinguish normal fracture healing from abnormal healing or nonunion in humans are unknown. This study was an exploratory investigation of peripheral blood from acutely injured fracture patients collected over multiple days to compare normal healers, slow healers, and nonunion outcomes. We used microarrays to do a global comparison between acutely injured (AI) subjects (AIS) vs. age- and sex-matched healthy volunteers (HV) and chronic Nonunion (NU) patients.

2017-01-11 | GSE93378 | GEO

miRNA expression during fracture healing in diabetic rats

Project description:The association between DM and impaired fracture healing including delayed union and nonunion has been documented in clinical and experimental settings. We examine miRNA expression specific for impaired fracture healing in diabetic rat.

2017-01-15 | GSE76365 | GEO

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