Recombinant thrombomodulin lectin-like domain attenuates porphyromonas gingivalis lipopolysaccharide-induced osteoclastogenesis and periodontal bone resorption
Recombinant thrombomodulin lectin-like domain attenuates porphyromonas gingivalis lipopolysaccharide-induced osteoclastogenesis and periodontal bone resorption
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DOI：
10.1002/jper.20-0732
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发表时间：
2021-02-06
影响因子：
4.3
通讯作者：
Cheng, Tsung-Lin
中科院分区：
文献类型：
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作者：
Chang, Lan-Yun;Lai, Chao-Han;Cheng, Tsung-Lin
研究背景血栓调节蛋白（TM）凝集素结构域（TMD 1）具有抗炎作用。牙龈卟啉单胞菌（Porphyromonas gingivalis，Pg-LPS）的脂多糖（Lipopolysaccharides）是慢性牙周炎的主要致病因子，可促进炎症反应、破骨细胞生成和牙槽骨吸收。在此，我们的目的是评估潜在的治疗效果的重组TMD 1（rTMD 1）在抑制Pg-LPS诱导的破骨细胞和牙周bone loss.Methods在体外，Pg-LPS，肿瘤坏死因子（TNF）-α和rTMD 1对破骨细胞分化的影响进行了研究使用核因子-κ B配体受体激活剂（RANKL）刺激的RAW 264.7巨噬细胞。结果给予RANKL刺激的RAW 264.7巨噬细胞Pg-LPS导致CD 86和破骨细胞标志物（例如，Dc-stamp和Trap）基因表达上调，促炎细胞因子产生增加（例如，TNF-α）在破骨细胞分化过程中的作用，而rTMD 1可以减弱这些作用。此外，rTMD 1抑制Pg-LPS增强的体外骨吸收以剂量依赖性的方式。此外，TNF-α在破骨细胞分化过程中促进p38和ERK的磷酸化，并且该信号激活可被rTMD 1抑制。结论rTMD 1能抑制Pg-LPS诱导的M1巨噬细胞极化、破骨细胞生成和牙周骨吸收，对牙周炎有治疗作用。
Background Evidence demonstrates that the thrombomodulin (TM) lectin domain (TMD1) exerts anti-inflammatory functions. Lipopolysaccharides derived from Porphyromonas gingivalis (Pg-LPS) are considered a major pathogenic factor for chronic periodontitis, promoting inflammation, osteoclastogenesis and alveolar bone resorption. Herein, we aimed to evaluate the potential therapeutic effect of recombinant TMD1 (rTMD1) in suppression of Pg-LPS-induced osteoclastogenesis and periodontal bone loss.Methods In vitro, the effects of Pg-LPS, tumor necrosis factor (TNF)-alpha and rTMD1 on osteoclast differentiation were investigated using receptor activator of nuclear factor-kappa B ligand (RANKL)-stimulated RAW 264.7 macrophages. In vivo, the effects of rTMD1 treatment were evaluated in a model of experimental periodontitis induced by direct injection of Pg-LPS into the vestibular gingiva.Results Administration of Pg-LPS to RANKL-stimulated RAW 264.7 macrophages resulted in upregulation of CD86 and osteoclast marker (eg, Dc-stamp and Trap) gene expression and increase of pro-inflammatory cytokine production (e.g., TNF-alpha) during osteoclast differentiation, and rTMD1 can attenuate these effects. Also, rTMD1 inhibited Pg-LPS-enhanced in vitro bone resorption in a dose-dependent manner. Moreover, TNF-alpha promoted phosphorylation of p38 and ERK during osteoclast differentiation, and the signal activation can be inhibited by rTMD1. Finally, treatment with rTMD1 hindered Pg-LPS-induced alveolar bone loss in experimental periodontitis in mice.Conclusion Our study demonstrated that rTMD1 attenuates Pg-LPS-enhanced M1 macrophage polarization, osteoclastogenesis and periodontal bone resorption and thus holds therapeutic promise for periodontitis.