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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

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

2017-01-06 | GSE93216 | GEO

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

2017-01-06 | GSE93217 | GEO

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

2017-01-11 | GSE93387 | GEO

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

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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

mRNA 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 mRNA expression specific for impaired fracture healing in diabetic rat.

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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

809094 Biomarker Identification in Fracture Healing (experiment #4068 performed)

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 compared to age- and sex-matched healthy volunteers. Bone fragments were collected from acutely injured subjects during surgery through the Cooperative Human Tissue Network-Eastern Division (CHTN-ED http://pathology.med.upenn.edu/research/centers-and-institutes/cooperative-human-tissue-network). We used microarrays to do a global comparison between acutely injured (AI) subjects (AIS) and chronic Nonunion (NU) subjects vs. age- and sex-matched healthy volunteers (HV). We also compared tissue types by capturing bone fragments from the fracture site where possible.

2017-01-11 | GSE93390 | GEO

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