Increased expression of angiopoietin‐like protein 4 regulates matrix metalloproteinase‐13 expression in Porphyromonas gingivalis lipopolysaccharides‐stimulated gingival fibroblasts and ligature‐induced experimental periodontitis

• Published in: Journal of periodontal research 2023-02, Vol.58 (1), p.43-52
• Main Authors: Kondo, Shun, Kojima, Kento, Nakamura, Nobuhisa, Miyabe, Megumi, Kikuchi, Takeshi, Ohno, Tasuku, Sawada, Noritaka, Minato, Tomomi, Saiki, Tomokazu, Ito, Mizuho, Sasajima, Sachiko, Matsubara, Tatsuaki, Mitani, Akio, Naruse, Keiko
• Format: Article
• Language: English
• Subjects: Angiopoietin; Angiopoietin-Like Protein 4 - metabolism; ANGPTL4; Animals; Cells, Cultured; Collagenase 3; Fibroblasts; Fibroblasts - metabolism; Gene expression; Gingiva; Gingiva - metabolism; gingival fibroblasts; Gum disease; Humans; Hypoxia; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Male; Matrix metalloproteinase; Matrix Metalloproteinase 13 - metabolism; Matrix Metalloproteinase 13 - pharmacology; Metalloproteinase; MMP; Periodontal ligament; Periodontitis; Periodontitis - metabolism; Porphyromonas gingivalis; Proteins; Rats; Rats, Sprague-Dawley; siRNA
• ISSN: 0022-3484; 1600-0765
• DOI: 10.1111/jre.13067

Background Angiopoietin‐like protein 4 (ANGPTL4) is produced in chronic or acute inflammation. Although ANGPTL4 increases in the periodontal ligament fibroblasts during hypoxia, the involvement and role of ANGPTL4 in periodontitis have not been elucidated. Objective In this study, we investigated whether ligature‐induced experimental periodontitis and/or Porphyromonas gingivalis lipopolysaccharides (Pg‐LPS) would upregulate ANGPTL4 expression and whether ANGPTL4 would somehow involve in the expression of matrix metalloproteinases (MMPs) which are key molecules in the process of periodontal tissue destruction. Methods Experimental periodontitis was induced in 6‐week‐old male Sprague–Dawley rats by placing a nylon suture around the neck of the maxillary second molar. Two weeks after the induction of periodontitis, the periodontal tissue was excised and analyzed by histological/immunohistochemical staining and gene expression analyses. Human gingival fibroblasts (hGFs) were stimulated with Pg‐LPS. The gene expression of ANGPTLs and receptors involved in ANGPTL4 recognition were observed. We also confirmed the changes in gene expression of MMPs upon stimulation with human ANGPTL4. Furthermore, we downregulated ANGPTL4 expression by short interfering RNA in hGFs and investigated the effect of Pg‐LPS on MMP production. Results Induction of periodontitis significantly increased the expression of ANGPTL4 in the gingiva. Pg‐LPS significantly increased the gene and protein expression of ANGPTL4 in hGFs but not the gene expression of other ANGPTLs or ANGPTL receptors. Recombinant human ANGPTL4 significantly increased MMP13 gene expression in hGFs. We also confirmed that MMP13 expression was increased in the gingiva during experimental periodontitis. Pg‐LPS induced MMP13 gene expression in hGFs. These results suggest the pivotal role of ANGPTL4 in periodontitis. Conclusion Periodontitis increases ANGPTL4 expression in the gingiva, further suggesting that increased ANGPTL4 may be a factor involved in enhancing MMP13 expression.