Background
Tooth movement is a unique bone remodeling process induced by mechanical stimulation. Macrophages are important in mediating inflammatory processes during mechanical load-induced tooth movement. However, how macrophages are regulated under mechanical stimulation remains unclear. Mesenchymal stem cells (MSCs) can modulate macrophage polarization during bone remodeling. Hydrogen sulfide (H2S) can be produced by MSCs and have been linked to bone homeostasis. Therefore, this study aimed to investigate whether H2S contributed to periodontal ligament stem cell (PDLSC)-regulated macrophage polarization and bone remodeling under mechanical stimulation.
Methods
An experimental mechanical load-induced tooth movement animal model was established. Changes in cystathionine-β-synthase (CBS), markers of M1/M2 macrophages, tooth movement distance, and the number of osteoclasts were examined. The conditioned medium of PDLSCs with or without mechanical loading was utilized to treat THP-1 derived macrophages for 24 h to further investigate the effect of PDLSCs on macrophage polarization. Different treatments with H2S donor, CBS inhibitor, or the inhibitor of STAT1 were used to investigate the related mechanism. Markers of M1/M2 polarization and STAT1 pathway expression were evaluated in macrophages.
Results
Mechanical load promoted tooth movement and increased the number of M1-like macrophages, M1-associated pro-inflammatory cytokines, and the expression of CBS on the compression side of the periodontal ligament. The injection of CBS inhibitor or H2S donor could further repress or increase the number of M1-like macrophages, tartrate-resistant acid phosphatase-positive osteoclasts and the distance of tooth movement. Mechanistically, load-induced PDLSCs enhanced H2S production, which increased the expression of M1-associated cytokines in macrophages. These effects could be blocked by the administration of CBS inhibitor. Moreover, load-induced H2S steered M1 macrophage polarization via the STAT1 signaling pathway.
Conclusions
These data suggest a novel mechanism indicating that mechanical load-stimulated PDLSCs produce H2S to polarize macrophages toward the M1 phenotype via the STAT1 signaling pathway, which contributes to bone remodeling and tooth movement process. These results provide new insights into the role of PDLSCs in regulating macrophage polarization and mediating bone remodeling under mechanical stimulation, and indicate that appropriate H2S supplementation may accelerate tooth movement.
The interplay between mechanoresponses and a broad range of fundamental biological processes, such as cell cycle progression, growth and differentiation, has been extensively investigated. However, metabolic regulation in mechanobiology remains largely unexplored. Here, we identified glucose transporter 1 (GLUT1)—the primary glucose transporter in various cells—as a novel mechanosensitive gene in orthodontic tooth movement (OTM). Using an in vivo rat OTM model, we demonstrated the specific induction of Glut1 proteins on the compressive side of a physically strained periodontal ligament. This transcriptional activation could be recapitulated in in vitro cultured human periodontal ligament cells (PDLCs), showing a time- and dose-dependent mechanoresponse. Importantly, application of GLUT1 specific inhibitor WZB117 greatly suppressed the efficiency of orthodontic tooth movement in a mouse OTM model, and this reduction was associated with a decline in osteoclastic activities. A mechanistic study suggested that GLUT1 inhibition affected the receptor activator for nuclear factor-κ B Ligand (RANKL)/osteoprotegerin (OPG) system by impairing compressive force-mediated RANKL upregulation. Consistently, pretreatment of PDLCs with WZB117 severely impeded the osteoclastic differentiation of co-cultured RAW264.7 cells. Further biochemical analysis indicated mutual regulation between GLUT1 and the MEK/ERK cascade to relay potential communication between glucose uptake and mechanical stress response. Together, these cross-species experiments revealed the transcriptional activation of GLUT1 as a novel and conserved linkage between metabolism and bone remodelling.
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