NLRP3 deficiency improves bone healing of tooth extraction sockets through SMAD2/3-RUNX2-mediated osteoblast differentiation

• Published in: Stem cells (Dayton, Ohio) Ohio), 2024-12, Vol.42 (12), p.1085
• Main Authors: Geng, Ying, Bao, Chen, Chen, Yue, Yan, Ziwei, Miao, Fen, Wang, Ting, Li, Yingyi, Li, Lu, Sun, Wen, Xu, Yan
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; Inflammasomes - metabolism; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Osteoblasts - metabolism; Osteogenesis; Signal Transduction; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Tooth Extraction; Tooth Socket; Wound Healing
• ISSN: 1066-5099; 1549-4918; 1549-4918
• DOI: 10.1093/stmcls/sxae064

Impaired bone healing following tooth extraction poses a significant challenge for implantation. As a crucial component of the natural immune system, the NLRP3 inflammasome is one of the most extensively studied pattern-recognition receptors, and is involved in multiple diseases. Yet, the role of NLRP3 in bone healing remains to be clarified. Here, to investigate the effect of NLRP3 on bone healing, we established a maxillary first molar extraction model in wild-type and NLRP3KO mice using minimally invasive techniques. We observed that NLRP3 was activated during the bone repair phase, and its depletion enhanced socket bone formation and osteoblast differentiation. Moreover, NLRP3 inflammasome activation was found to inhibit osteogenic differentiation in alveolar bone-derived mesenchymal stem cells (aBMSCs), an effect mitigated by NLRP3 deficiency. Mechanistically, we established that the SMAD2/3-RUNX2 signaling pathway is a downstream target of NLRP3 inflammasome activation, and SMAD2/3 knockdown partially reversed the significant decrease in expression of RUNX2, OSX, and ALP induced by NLRP3. Thus, our findings demonstrate that NLRP3 negatively modulates alveolar socket bone healing and contributes to the understanding of the NLRP3-induced signaling pathways involved in osteogenesis regulation.