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Pmepa1 knockdown alleviates SpA-induced pyroptosis and osteogenic differentiation inhibition of hBMSCs via
Mingjun Li1, Xiangwen Shi1, Yipeng Wu2
1Kunming Medical University, Kunming, Yunnan 650500, China.
Background:
Osteomyelitis is a refractory bone infectious disease, which usually results in progressive bone destruction and bone loss. The invasion of pathogens and subsequent inflammatory response could damage bone marrow mesenchymal stem cells (BMSCs) and inhibit osteogenic differentiation, and finally aggravate uncontrolled bone remodeling in osteomyelitis by affecting bone formation. Exploring the mechanisms of BMSCs injury and osteogenic differentiation inhibition may would help us to find potential therapeutic targets.
Method:
Firstly, staphylococcal protein A (SpA)-treated human bone marrow mesenchymal stem cells (hBMSCs) were used to construct cell models of osteomyelitis. Secondly, transcriptome sequencing was performed to screen differentially expressed genes and then verified the expression of target genes. Next, in vitro experiments were conducted to explore the functions and mechanisms of prostate transmembrane protein androgen induced 1 (Pmepa1) in SpA-treated hBMSCs. Finally, the rat model of osteomyelitis was established to provide an auxiliary validation of the in vitro experimental results.
Results:
We found that SpA treatment induced inflammatory injury and inhibited osteogenic differentiation in hBMSCs, then the transcriptome sequencing and further detection results showed that Pmepa1 was significantly upregulated in this process. Functionally, Pmepa1 knockdown alleviated inflammatory injury and promoted osteogenic differentiation in SpA-treated hBMSCs. Among them, it was demonstrated that Pmepa1 knockdown exerted cytoprotective effects by alleviating pyroptosis of SpA-infected hBMSCs. Furthermore, recovery experiments revealed that Pmepa1 knockdown reversed SpA-mediated adverse effects by downregulating the p38MAPK/NLRP3 axis. Finally, the detection results of rat femoral osteomyelitis showed that the expression of Pmepa1 was up-regulated, and the expression trends of other indicators including p38MAPK, NLRP3, and caspase-1 were also consistent with the in vitro model.
Conclusion:
Pmepa1 knockdown alleviates SpA-induced pyroptosis and inhibition of osteogenic differentiation in hBMSCs by downregulating p38MAPK/NLRP3 signaling axis. Modulating the expression of Pmepa1 may be a potential strategy to ameliorate osteomyelitis.
Insights
Reducing prostate transmembrane protein androgen induced 1 (Pmepa1) helps bone marrow mesenchymal stem cells (BMSCs) resist osteomyelitis. Knocking down Pmepa1 alleviates inflammation and promotes bone formation by downregulating the p38MAPK/NLRP3 pathway.
Area of Science:
- Biomedical Science
- Cell Biology
- Molecular Biology
Background:
- Osteomyelitis is a severe bone infection causing destruction and loss.
- Pathogen invasion and inflammation damage bone marrow mesenchymal stem cells (BMSCs), inhibiting osteogenic differentiation and worsening bone remodeling.
- Understanding BMSC injury mechanisms in osteomyelitis is crucial for identifying therapeutic targets.
Purpose of the Study:
- To investigate the role of prostate transmembrane protein androgen induced 1 (Pmepa1) in osteomyelitis.
- To explore the mechanisms by which Pmepa1 affects human bone marrow mesenchymal stem cells (hBMSCs) during osteomyelitis.
- To evaluate Pmepa1 as a potential therapeutic target for osteomyelitis.
Main Methods:
- Established osteomyelitis cell models using staphylococcal protein A (SpA)-treated hBMSCs.
- Utilized transcriptome sequencing to identify differentially expressed genes, focusing on Pmepa1.
- Conducted in vitro experiments and established a rat osteomyelitis model to validate findings.
- Investigated the function and mechanism of Pmepa1 in SpA-treated hBMSCs, including its effect on pyroptosis and the p38MAPK/NLRP3 axis.
Main Results:
- SpA treatment induced inflammation and inhibited osteogenic differentiation in hBMSCs, with significant upregulation of Pmepa1.
- Knockdown of Pmepa1 alleviated inflammatory injury, promoted osteogenic differentiation, and reduced pyroptosis in SpA-treated hBMSCs.
- Pmepa1 knockdown reversed SpA-induced adverse effects by downregulating the p38MAPK/NLRP3 signaling axis.
- In vivo validation in a rat model confirmed increased Pmepa1 expression and consistent trends in p38MAPK, NLRP3, and caspase-1.
Conclusions:
- Pmepa1 knockdown ameliorates SpA-induced pyroptosis and osteogenic differentiation inhibition in hBMSCs via the p38MAPK/NLRP3 pathway.
- Modulating Pmepa1 expression presents a potential therapeutic strategy for osteomyelitis.
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