Prophylactic Effects of NFκB Essential Modulator–Binding Domain Peptides on Bone Infection: An Experimental Study in a Rabbit Model

Wu, Wenjiao; Xia, Changliang; Ou, Shuanji; Yang, Yang; Zhou, Xiaozhong; Ma, You-Zhi; Hou, Yilong; Wang, Fa-Zheng; Yang, Qing‐Po; Qi, Yong; Xu, Changpeng

doi:10.2147/jir.s346627

Cited by 3 publications

(3 citation statements)

References 36 publications

(54 reference statements)

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“…Although the discovery of pyroptosis has provided a potential new strategy for treating inflammatory conditions, such as bone inflammation, the specific molecular mechanisms have not yet been elucidated. The NOD‐like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation is a potential molecular mechanism underlying pyroptosis that is thought to affect various diseases, including osteomyelitis, Alzheimer's disease and Type II diabetes 16–19 …”

Section: Introductionmentioning

confidence: 99%

“…The NOD‐like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation is a potential molecular mechanism underlying pyroptosis that is thought to affect various diseases, including osteomyelitis, Alzheimer's disease and Type II diabetes. 16 , 17 , 18 , 19 …”

Section: Introductionmentioning

confidence: 99%

“…The NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation is a potential molecular mechanism underlying pyroptosis that is thought to affect various diseases, including osteomyelitis, Alzheimer's disease and Type II diabetes. [16][17][18][19] MC3T3-E1 has been used to explore osteoblast differentiation. [20][21][22] Based on the results of our previous studies, we hypothesized that ELP2 promotes the deleterious effects of TNF-α-induced pyroptosis during osteoblastic differentiation in MC3T3-E1 cells.…”

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confidence: 99%

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ELP2‐NLRP3‐GSDMD/GSDME‐mediated pyroptosis is induced by TNF‐α in MC3T3‐E1 cells during osteogenic differentiation

Xia,

Ou,

Yang

et al. 2023

J Cellular Molecular Medi

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Tumour necrosis factor‐α (TNF‐α) is a cytokine involved in systemic inflammation. TNF‐α slows down osteogenic differentiation, which may contribute to poor bone development in the inflammatory microenvironment. TNF‐α inhibits osteogenic differentiation by activating the JAK‐STAT3 pathway, of which Signal transducer and activator of transcription 3 (STAT3)‐interacting protein 1 (StIP1, also known as elongator complex protein 2, ELP2) is a key protein in the JAK‐STAT3 pathway. We investigated whether and how ELP2 activation mediates the TNF‐α‐induced pyroptosis during osteoblastic differentiation. Using in vitro cell cultures of preosteoblastic MC3T3‐E1 cells, we found that TNF‐α exposure causes cell pyroptosis in an inflammatory microenvironment during osteoblastic differentiation. Bioinformatics, protein docking model and co‐immunoprecipitation analysis revealed an association between ELP2, STAT3 and NLRP3. Forced ELP2 expression promoted MC3T3‐E1 cells pyroptosis, with an increase in the expression of STAT3, NLRP3 inflammasome, GSDMD/GSDME, osteoblast marker genes, and the activity of alkaline phosphatase. In contrast, ELP2 silencing ameliorated MC3T3‐E1 cells pyroptosis, and osteogenic differentiation, especially after TNF‐α stimulation. The TNF‐α‐induced cells pyroptosis during osteoblastic differentiation was therefore mediated by ELP2. These results suggest that ELP2 is upregulated at the pyroptosis of MC3T3‐E1 cells and inhibits osteogenic differentiation in response to TNF‐α through NLRP3‐GSDMD/GSDME activation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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ELP2‐NLRP3‐GSDMD/GSDME‐mediated pyroptosis is induced by TNF‐α in MC3T3‐E1 cells during osteogenic differentiation

Xia,

Ou,

Yang

et al. 2023

J Cellular Molecular Medi

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Dual-Functionalized Injectable pH-Responsive Hydrogels Loaded with Magnesium Peroxide for the Treatment of Implant-Associated Infection

Peng,

Du,

Song

et al. 2024

ACS Appl. Mater. Interfaces

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Implant-associated infections frequently complicate orthopedic surgeries, resulting in challenging issues. The current therapy of antibiotic treatment and surgical debridement often leads to drug resistance and bone defect. The development of pH-responsive antimicrobial and pro-osteogenic materials is a promising approach to controlling infections and repairing infected bone defects, especially given the weakly acidic pH of the bacterial infection area. Solid peroxides have the potential to provide a sustained release of hydrogen peroxide (H 2 O 2 ), rendering them applicable for antimicrobial purposes. Additionally, their chemical properties render them inherently responsive to pH. Here, we propose a novel GelBA/PVA/MgO 2 hydrogel composed of gelatin (Gel), benzeneboronic acid (BA), poly(vinyl alcohol) (PVA), and magnesium peroxide (MgO 2 ) with self-healing ability and pH-responsiveness. The borate ester bond formed between PVA and BA is a dynamic chemical bond with properties of dynamic formation and dissociation, making the hydrogel both self-healable and pH-responsive. Meanwhile, the addition of MgO 2 improves the network structure of the hydrogel and gives the hydrogel the ability to perform sustained release of H 2 O 2 and Mg 2+ . Experimentally, the GelBA/PVA/MgO 2 hydrogel exhibits controlled and pH-dependent H 2 O 2 and Mg 2+ release, sustained over time at physiological pH (7.4) and significantly increased at infection pH (5.5). In vitro and in vivo outcomes revealed that this hydrogel is able to inhibit Staphylococcus aureus growth and accelerate bone regeneration, improving bone healing without cytotoxic effects on normal tissues. These findings suggest that the GelBA/PVA/MgO 2 hydrogel is a unique and efficient approach for anti-infection and therapeutic implant-associated infections.

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Establishment of a mandible defect model in rabbits infected with multiple bacteria and bioinformatics analysis

Zhao,

Su,

et al. 2024

Front. Bioeng. Biotechnol.

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Objective: A model of chronic infectious mandibular defect (IMD) caused by mixed infection with Staphylococcus aureus and Pseudomonas aeruginosa was established to explore the occurrence and development of IMD and identify key genes by transcriptome sequencing and bioinformatics analysis.Methods:S. aureus and P. aeruginosa were diluted to 3 × 108 CFU/mL, and 6 × 3 × 3 mm defects lateral to the Mandibular Symphysis were induced in 28 New Zealand rabbits. Sodium Morrhuate (0.5%) and 50 μL bacterial solution were injected in turn. The modeling was completed after the bone wax closed; the effects were evaluated through postoperative observations, imaging and histological analyses. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein‒protein interaction (PPI) network analyses were performed to investigate the function of the differentially expressed genes (DEGs).Results: All rabbits showed characteristics of infection. The bacterial cultures were positive, and polymerase chain reaction (PCR) was used to identify S. aureus and P. aeruginosa. Cone beam CT and histological analyses showed inflammatory cell infiltration, pus formation in the medullary cavity, increased osteoclast activity in the defect area, and blurring at the edge of the bone defect. Bioinformatics analysis showed 1,804 DEGs, 743 were upregulated and 1,061 were downregulated. GO and KEGG analyses showed that the DEGs were enriched in immunity and osteogenesis inhibition, and the core genes identified by the PPI network were enriched in the Hedgehog pathway, which plays a role in inflammation and tissue repair; the MEF2 transcription factor family was predicted by IRegulon.Conclusion: By direct injection of bacterial solution into the rabbit mandible defect area, the rabbit chronic IMD model was successfully established. Based on the bioinformatics analysis, we speculate that the Hedgehog pathway and the MEF2 transcription factor family may be potential intervention targets for repairing IMD.

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Prophylactic Effects of NFκB Essential Modulator–Binding Domain Peptides on Bone Infection: An Experimental Study in a Rabbit Model

Cited by 3 publications

References 36 publications

ELP2‐NLRP3‐GSDMD/GSDME‐mediated pyroptosis is induced by TNF‐α in MC3T3‐E1 cells during osteogenic differentiation

ELP2‐NLRP3‐GSDMD/GSDME‐mediated pyroptosis is induced by TNF‐α in MC3T3‐E1 cells during osteogenic differentiation

Dual-Functionalized Injectable pH-Responsive Hydrogels Loaded with Magnesium Peroxide for the Treatment of Implant-Associated Infection

Establishment of a mandible defect model in rabbits infected with multiple bacteria and bioinformatics analysis

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