Department of Conservation Dentistry and Endodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China.
Department of Conservation Dentistry and Endodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China.
Exp Cell Res. 2018 Nov 15;372(2):178-187. doi: 10.1016/j.yexcr.2018.09.024. Epub 2018 Oct 1.
Oral diseases, such as periapical periodontitis and periodontitis, are characterized by inflammation-induced bone loss. LL-37, a human antimicrobial peptide (AMP), has multiple biological functions and the potential to promote osteogenesis. Therefore, this study aimed to investigate the regulatory effects of LL-37 within normal and inflammatory microenvironments. The roles of P2X7 receptor (P2X7R) and mitogen-activated protein kinase (MAPK) signaling pathway were also demonstrated. The results showed that LL-37 promoted bone marrow stromal cell (BMSC) proliferation, migration and osteogenic differentiation. LL-37 inhibited the expression of the inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and receptor activator of nuclear factor kappa-B ligand (RANKL) at both protein and gene levels, and attenuated the lipopolysaccharide (LPS)-induced inhibition of osteogenesis. Immunofluorescence (IF) confirmed P2X7R expression in BMSCs. BBG, a P2X7R antagonist, significantly attenuated LL-37-promoted osteogenesis. The phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK) increased after LL-37 stimulation, which did not affect p38 phosphorylation. The effects of LL-37 on osteogenesis-related gene expression were markedly attenuated by selective inhibitors of ERK1/2 and JNK. Furthermore, a mouse model of LPS-stimulated calvarial osteolysis was established, and results showed that LL-37 markedly inhibited osteoclastic bone resorption. In conclusion, we speculate that LL-37 inhibits inflammation and promotes BMSC osteogenesis via P2X7R and MAPK signaling pathway.
口腔疾病，如根尖周炎和牙周炎，其特征为炎症引起的骨丢失。人抗菌肽（AMP）LL-37 具有多种生物学功能，并具有促进成骨的潜力。因此，本研究旨在探讨正常和炎症微环境中 LL-37 的调节作用。还证明了 P2X7 受体（P2X7R）和丝裂原活化蛋白激酶（MAPK）信号通路的作用。结果表明，LL-37 促进骨髓基质细胞（BMSC）增殖、迁移和成骨分化。LL-37 在蛋白和基因水平上抑制了炎症细胞因子白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和核因子κB 配体（RANKL）的表达，并减弱了脂多糖（LPS）诱导的成骨抑制作用。免疫荧光（IF）证实了 P2X7R 在 BMSCs 中的表达。P2X7R 拮抗剂 BBG 显著减弱了 LL-37 促进的成骨作用。LL-37 刺激后 ERK1/2 和 c-Jun NH2-末端激酶（JNK）的磷酸化增加，但不影响 p38 的磷酸化。ERK1/2 和 JNK 的选择性抑制剂显著减弱了 LL-37 对成骨相关基因表达的影响。此外，建立了 LPS 刺激的颅盖骨骨溶解小鼠模型，结果表明 LL-37 显著抑制破骨细胞的骨吸收。总之，我们推测 LL-37 通过 P2X7R 和 MAPK 信号通路抑制炎症并促进 BMSC 成骨。
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