Dnmt3b ablation impairs fracture repair through upregulation of Notch pathway

Ying, Jun; Xu, Taotao; Wang, Cuicui; Jin, Hongting; Tong, Peijian; Guan, Jianjun; Abu‐Amer, Yousef; O’Keefe, Regis J.; Shen, Jie

doi:10.1172/jci.insight.131816

Cited by 19 publications

(15 citation statements)

References 61 publications

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“…Images were acquired using ZEISS microscopy (Carl Zeiss Industrial Metrology, Maple Grove, MN). Cartilage area, bone area, mesenchyme area, and osteoclast parameters were quantified on ABH/OG, TRAP-stained sections using NIH ImageJ software 1.52a (Wayne Rasband) and Bioquant ( Ying et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling

Sun

Chün²,

Xiao³

et al. 2022

eLife

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IL-18. Excessive GSDM-mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment. Therefore, we tested the hypothesis that GSDMD and GSDME are implicated in fracture healing owing to their role in the obligatory inflammatory response following injury. We found that bone callus volume and biomechanical properties of injured bones were significantly reduced in mice lacking either GSDM compared with wild-type (WT) mice, indicating that fracture healing was compromised in mutant mice. However, compound loss of GSDMD and GSDME did not exacerbate the outcomes, suggesting shared actions of both GSDMs in fracture healing. Mechanistically, bone injury induced IL-1β and IL-18 secretion in vivo, a response that was mimicked in vitro by bone debris and ATP, which function as inflammatory danger signals. Importantly, the secretion of these cytokines was attenuated in conditions of GSDMD deficiency. Finally, deletion of IL-1 receptor reproduced the phenotype of Gsdmd or Gsdme deficient mice, implying that inflammatory responses induced by the GSDM-IL-1 axis promote bone healing after fracture.

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Section: Methodsmentioning

confidence: 99%

Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling

Sun

Chün²,

Xiao³

et al. 2022

eLife

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“…In Table 2, shared pathways with genes deregulated by VPA and downregulated in models of causative genes for KLEFS, KS, CHARGE, MRD1, and ARTHS or ICF1 are summarized (Katsumoto et al, 2006;Issaeva et al, 2007;Min et al, 2007;Fan, 2008;Gupta-Agarwal et al, 2012;Mansour et al, 2012;Balemans et al, 2014;Chen et al, 2014;Kim et al, 2014;Schulz et al, 2014;Turner-Ivey et al, 2014;Gigek et al, 2015;Dhar et al, 2016Dhar et al, , 2018Fang et al, 2016;Mullegama et al, 2016;Sheikh et al, 2016Sheikh et al, , 2017Feng et al, 2017a,b;Shpargel et al, 2017;Whittaker et al, 2017;Baell et al, 2018;Marie et al, 2018;Yao et al, 2018Yao et al, , 2020Carosso et al, 2019;Machado et al, 2019;Nowialis et al, 2019;Cieslar-Pobuda et al, 2020;Frega et al, 2020;Hsu et al, 2020;Kong et al, 2020;Liu et al, 2020;Xu et al, 2020;Ying et al, 2020;Fei et al, 2021;Lopusna et al, 2021). Of note, the most commonly shared pathways involve either morphogenesis signals (for example, beta1 integrin cell surface interactions and extracellular matrix organization), or possible defects of the central nervous system (such as axon guidance and neuro...…”

Section: Shared Epigenetic and Gene Expression Alterationsmentioning

confidence: 99%

Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies

Parodi

Fede

Peron

et al. 2021

Front. Cell Dev. Biol.

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Prenatal exposure to valproate (VPA), an antiepileptic drug, has been associated with fetal valproate spectrum disorders (FVSD), a clinical condition including congenital malformations, developmental delay, intellectual disability as well as autism spectrum disorder, together with a distinctive facial appearance. VPA is a known inhibitor of histone deacetylase which regulates the chromatin state. Interestingly, perturbations of this epigenetic balance are associated with chromatinopathies, a heterogeneous group of Mendelian disorders arising from mutations in components of the epigenetic machinery. Patients affected from these disorders display a plethora of clinical signs, mainly neurological deficits and intellectual disability, together with distinctive craniofacial dysmorphisms. Remarkably, critically examining the phenotype of FVSD and chromatinopathies, they shared several overlapping features that can be observed despite the different etiologies of these disorders, suggesting the possible existence of a common perturbed mechanism(s) during embryonic development.

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“…Images were acquired using ZEISS microscopy (Carl Zeiss Industrial Metrology, MN). Cartilage area, bone area, mesenchyme area, and osteoclast parameters were quantified on ABH/OG, TRAP-stained sections using NIH ImageJ software 1.52a (Wayne Rasband) and Bioquant (41).…”

Section: Histological Analyses Of Fracture Callusesmentioning

confidence: 99%

Fracture healing is delayed in the absence of gasdermin signaling

Mbalaviele

Sun

Wang

et al. 2021

Preprint

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Amino-terminal fragments from proteolytically cleaved gasdermins (GSDMs) form plasma membrane pores that enable the secretion of interleukin-1β (IL-1β) and IL-18. Excessive GSDM- mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment. Therefore, we tested the hypothesis that GSDMD and GSDME are implicated in fracture healing owing to their role in the obligatory inflammatory response following injury. We found that bone callus volume and biomechanical properties of injured bones were significantly reduced in mice lacking either GSDM compared with wild-type (WT) mice, indicating that fracture healing was compromised in mutant mice. However, compound loss of GSDMD and GSDME did not exacerbate the outcomes, suggesting shared actions of both GSDMs in fracture healing. Mechanistically, bone injury induced IL-1β and IL-18 secretion in vivo, a response that was mimicked in vitro by bone debris and ATP, which function as inflammatory danger signals. Importantly, the secretion of these cytokines was attenuated in conditions of GSDMD deficiency. Finally, deletion of IL-1 receptor reproduced the phenotype of Gsdmd or Gsdme deficient mice, implying that inflammatory responses induced by the GSDM-IL-1 axis promote bone healing after fracture.

show abstract

Dnmt3b ablation impairs fracture repair through upregulation of Notch pathway

Cited by 19 publications

References 61 publications

Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling

Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling

Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies

Fracture healing is delayed in the absence of gasdermin signaling

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