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The Effect of Diabetic Medicine Exendin-4 on Lipopolysaccharide-induced Bone Resorption, Osteoclast Formation, and Orthodontic Tooth Movement

沈 威任 東北大学

2020.09.25

概要

Glucagon-like peptide-1 (GLP-1) receptor agonists are an effective treatment approach for type 2 diabetes. Recently, anti-inflammatory effects of GLP-1 receptor agonists have also been reported. Lipopolysaccharide (LPS) induces inflammation and osteoclast formation. At first, we investigated the effect of exendin-4, a widely used GLP-1 receptor agonist, in LPS-induced osteoclast formation and bone resorption. LPS with or without exendin-4 was administered on mouse calvariae by daily subcutaneous injection. The number of osteoclasts (p<0.01), the ratio of bone resorption pits (p<0.05) and the level of C-terminal cross-linked telopeptide of type I collagen (CTX) (p<0.01) were significantly lower in LPS and exendin-4 co-administered mice than in mice administered LPS alone. RANKL (p<0.05) and TNF-α (p<0.01) mRNA expression levels were lower in the exendin-4 and LPS co-administered group than in the LPS-administered group. Our in vitro results showed no direct effects of exendin-4 on RANKL-induced osteoclast formation, TNF-α-induced osteoclast formation, or LPS-induced RANKL expression in stromal cells. Conversely, TNF-α mRNA expression was inhibited in the exendin-4 and LPS co-treated macrophages compared with cells treated with LPS alone (p<0.01). These results indicate that the GLP-1 receptor agonist exendin-4 may inhibit LPS-induced osteoclast formation and bone resorption by inhibiting LPS-induced TNF-α production in macrophages.

 Orthodontic patients with diabetes mellitus are increasing due to global population aging and poor dietary management, so it is crucial to understand the effect of diabetes medicine on orthodontic tooth movement. Exendin-4, a GLP-1 receptor agonist, is a subcutaneously administered medicine for type II diabetic patients with less side effects. The second purpose of this study was to investigate the effects of exendin-4 on orthodontic tooth movement distance, root resorption and expressions of osteoclast-related cytokines.

 A 10 gm NiTi coil spring was placed between the anterior alveolar bone and upper left first molar of each eight-week-old male C57BL/6 mouse. 20 μl exendin-4 solutions (containing 0.2 μg, 4 𝜇g or 20 𝜇g exendin-4) or PBS solution was injected on the buccal side of upper left first molar respectively every two days (n=4). After sacrifice on twelfth day, silicone impressions were taken to record tooth movement distance. 20 𝜇g exendin-4 injection group had lower orthodontic tooth movement distance than PBS injection group (p<0.01). The left maxillae of PBS and 20 𝜇g exendin-4 injection groups were also excised for histological analysis and RT-PCR analysis. Compared to PBS group, 20 𝜇g exendin-4 injection group showed lower osteoclast number (p<0.05), and odontoclast number (p<0.05), and root resorption surface percentage (p<0.05). The maxillae with 20 μg exendin-4 injections also had lower RANKL mRNA expression (p<0.05), TNF-α mRNA expression (p<0.05), and RANKL/OPG ratio (p<0.01) than the maxillae with PBS injections. There was no difference in the expression of OPG mRNA.

 Exendin-4 inhibits orthodontic tooth movement, so more attention should be paid to orthodontic patients who take exendin-4 for diabetes treatment. Since exendin-4 prevents orthodontic root resorption, GLP-1 receptor may be a treatment target for clinical cases with severe root resorption.

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