Effects of Erythromycin on Osteoclasts and Bone Resorption via DEL-1 Induction in Mice

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.

Application of Ligature-Induced Periodontitis in Mice to Explore the Molecular Mechanism of Periodontal Disease

“…Systemic antibiotic therapy can enhance the effect of mechanical debridement in overcoming periodontal infections, resulting in clinical improvements, such as a decrease in bleeding on probing, reduction in pocket depth, and gain in clinical attachment level [201,202]. Several reports have demonstrated the effects of systemic antibiotics in a ligature-induced periodontitis mouse model [203][204][205].…”

“…ERM has also been reported to affect osteoclasts and alveolar bone resorption via DEL-1 induction in ligated mice. Treatment with ERM inhibited alveolar bone loss by increasing Del1 expression and decreasing the expression of osteoclast-related factors, such as a nuclear factor of activated T cells (Nfatc1), a receptor activator of nuclear factor-κB (Tnfrsf11a), acid phosphatase 5 (Acp5), and cathepsin K (Ctsk) [205].…”

Neutrophil elastase aggravates periodontitis by disrupting gingival epithelial barrier via cleaving cell adhesion molecules

“…Briefly, mice randomly divided and anesthetized with 2–3% isoflurane through a nose mask were ligated with a 5-0 silk ligature around the maxillary second molar to induce periodontitis. The sample size (5 mice per group for each experiment) was set as in the previous study 37 , 38 . Ligation was performed on one mouse from each group in turn to minimize potential confounders.…”

Osteoimmunology in Periodontitis: Local Proteins and Compounds to Alleviate Periodontitis

“…DEL-1 also works as a central regulator of immune homeostasis and is a significant protein in the bone marrow niche that induces an emergency myelopoiesis for host immunity [ 140 ]. These abilities allow DEL-1 to control the immune responses, which reveal the remarkable effects in suppressing osteoclasts, alleviating inflammation, and promoting osteoblastogenesis in the periodontitis-induced mouse model [ 141 , 142 , 143 ] and non-human primates in animal studies [ 144 ]. DEL-1 is an anticipated periodontitis therapeutic agent against periodontitis, which removes the dependence on antimicrobial agents [ 145 ].…”