Force-Induced H₂S by PDLSCs Modifies Osteoclastic Activity during Tooth Movement

Hydrogen sulfide (H₂S), a gasotransmitter, has been recently linked to mesenchymal stem cell (MSC) function and bone homeostasis. Periodontal ligament stem cells (PDLSCs) are the main MSCs in PDL, which respond to mechanical force to induce physiological activities during orthodontic tooth movement (OTM). However, it is unknown whether mechanical force might induce endogenous H₂S production by PDLSCs to regulate alveolar bone homeostasis. Here, we used a mouse OTM model to demonstrate that orthodontic force-induced endogenous H₂S production in PDL tissue was associated with macrophage accumulation and osteoclastic activity in alveolar bone. Then, we showed that mechanical force application induced cystathionine β-synthase (CBS) expression and endogenous H₂S production by PDLSCs. Moreover, blocking endogenous H₂S or systemically increasing H₂S levels could decrease or enhance force-induced osteoclastic activities to control tooth movement. We further revealed how force-induced H₂S production by PDLSCs contributed to the secretion of monocyte chemoattractant protein-1 (MCP-1) and the expression of receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) system by PDLSCs. The secretion and expression of these factors controlled macrophage migration and osteoclast differentiation. This study demonstrated that PDLSCs produced H₂S to respond to and transduce force signals. Force-induced gasotransmitter H₂S production in PDLSCs therefore regulated osteoclastic activities in alveolar bone and controlled the OTM process through the MCP-1 secretion and RANKL/OPG system.