ArticleThe Journal of clinical investigation2023
DNA methylation-mediated Rbpjk suppression protects against fracture nonunion caused by systemic inflammation.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 11 citations in OpenAlex.
- Hyperprogressive disease in carcinoma induced by immune checkpoint inhibitor therapy: a systematic review.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Pooled it
- Preoperative neutrophil-to-lymphocyte ratio and refracture risk in hip fracture patients: a propensity score-matched analysis.Annals of medicine · 2026Article
- Review
- IL-1β/EPAS1-Associated Ferroptotic Stress Impairs Skeletal Stem/Progenitor Cell Function in Inflammation-Associated Fracture Nonunion.Current issues in molecular biology · 2026Article
- Retrotransposons in Bone and Joint Diseases.FASEB bioAdvances · 2026Review
- Spatial multi-omics decoding of the fracture nonunion niche: from immune-vascular-skeletal crosstalk to precision regeneration.Frontiers in medicine · 2026Review
- NFIA regulates articular chondrocyte fatty acid metabolism and joint homeostasis.Science translational medicine · 2025Article
- Current cutting-edge omics techniques on musculoskeletal tissues and diseases.Bone research · 2025Review
- Epigenetic Regulation of Bone Healing: Implications for Fracture Repair and Clinical Treatment Strategies.The Yale journal of biology and medicine · 2025Review
- The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions.Diseases (Basel, Switzerland) · 2025Review
- HERC5/ISG15 Enhances Glioblastoma Stemness and Tumor Progression by mediating SERBP1protein stability.Neuromolecular medicine · 2025Article
- Mechanisms and therapeutic prospect of the JAK-STAT signaling pathway in liver cancer.Molecular and cellular biochemistry · 2025Review
- Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing.Bioactive materials · 2024Article
- Vascular restoration through local delivery of angiogenic factors stimulates bone regeneration in critical size defects.Bioactive materials · 2024Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.