Abstract
Macrolides are used to treat various infectious diseases, including periodontitis. Furthermore, macrolides are known to have immunomodulatory effects; however, the underlying mechanism of their action remains unclear. DEL-1 has emerged as an important factor in homeostatic immunity and osteoclastogenesis. Specifically, DEL-1 is downregulated in periodontitis tissues. Therefore, in the present study, we investigated whether the osteoclastogenesis inhibitory effects of erythromycin (ERM) are mediated through upregulation of DEL-1 expression. We used a ligature-induced periodontitis model in C57BL/6Ncrl wild-type or DEL-1-deficient mice and in vitro cell-based mechanistic studies to investigate how ERM inhibits alveolar bone resorption. As a result of measuring alveolar bone resorption and gene expression in the tooth ligation model, ERM treatment reduced bone loss by increasing DEL-1 expression and decreasing the expression of osteoclast-related factors in wild-type mice. In DEL-1-deficient mice, ERM failed to suppress bone loss and gene expression of osteoclast-related factors. In addition, ERM treatment downregulated osteoclast differentiation and calcium resorption in in vitro experiments with mouse bone marrow-derived macrophages. In conclusion, ERM promotes the induction of DEL-1 in periodontal tissue, which may regulate osteoclastogenesis and decrease inflammatory bone resorption. These findings suggest that ERM may exert immunomodulatory effects in a DEL-1-dependent manner.
Highlights
Periodontitis is a disease characterized by inflammation and bone resorption caused by dysbiotic oral microflora, which in turn affects the periodontal tissue, resulting in tooth loss [1]
We demonstrated that developmental endothelial locus-1 (DEL-1) is a protein that is induced by macrolides and exerts immunomodulatory effects such as suppression of neutrophil migration [21]
Treatment with antibacterial drugs significantly decreased the number of aerobic and anaerobic bacteria attached to the ligature compared to that of the distilled water group (Figure S1b,c). These findings clearly indicate that the antibacterial property suppressed alveolar bone resorption in periodontitis
Summary
Periodontitis is a disease characterized by inflammation and bone resorption caused by dysbiotic oral microflora, which in turn affects the periodontal tissue, resulting in tooth loss [1]. Macrolides affect a wide range of immunological mechanisms, thereby providing immunomodulatory effects [13]. We demonstrated that developmental endothelial locus-1 (DEL-1) is a protein that is induced by macrolides and exerts immunomodulatory effects such as suppression of neutrophil migration [21]. We recently reported that erythromycin (ERM) exerts its immunomodulatory effects by regulating the local homeostatic factor DEL-1 and reduces bone resorption by inhibiting excessive infiltration of neutrophils in a mouse model [21]. It is not clear whether ERM-induced DEL-1 acts on osteoclasts. The effects of ERM and DEL-1 on osteoclast differentiation and bone resorption activity were investigated both in vitro and in vivo using wild-type (WT) or DEL-1-deficient mice
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