1. DNA methylation-mediated Rbpjk suppression protects against fracture nonunion caused by systemic inflammation
- Author
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Xiao, Ding, Fang, Liang, Liu, Zhongting, He, Yonghua, Ying, Jun, Qin, Haocheng, Lu, Aiwu, Shi, Meng, Li, Tiandao, Zhang, Bo, Guan, Jianjun, Wang, Cuicui, Abu-Amer, Yousef, and Shen, Jie
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DNA ,RNA sequencing ,Methylation ,Inflammation ,Genetic engineering ,RNA ,Methyltransferases ,Epigenetic inheritance ,Health care industry ,Washington University. School of Medicine - 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-[kappa]B/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., Introduction Under most circumstances, bone fractures regenerate with full restoration of tissue morphometry and mechanical strength in the absence of scar formation. Nonetheless, approximately 5% to 10% of fractures globally [...]
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- 2024
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