Abstract
Periodontal disease is one of the most prevalent chronic disorders worldwide. It is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss. Here, we focused on the role of adipokines, which are locally expressed by periodontal tissues, in the regulation of catabolic gene expression leading to periodontal inflammation. The expression of the nicotinamide phosphoribosyltransferase (NAMPT) adipokine was dramatically increased in inflamed human and mouse gingival tissues. NAMPT expression was also increased in lipopolysaccharide- and proinflammatory cytokine-stimulated primary cultured human gingival fibroblasts (GF). Adenovirus-mediated NAMPT (Ad-Nampt) overexpression upregulated the expression and activity of COX-2, MMP1 and MMP3 in human GF. The upregulation of IL-1β- or Ad-Nampt-induced catabolic factors was significantly abrogated by the intracellular NAMPT (iNAMPT) inhibitor, FK866 or by the sirtuin (SIRT) inhibitor, nicotinamide (NIC). Recombinant NAMPT protein or extracellular NAMPT (eNAMPT) inhibition using a blocking antibody did not alter NAMPT target gene expression levels. Moreover, intragingival Ad-Nampt injection mediated periodontitis-like phenotypes including alveolar bone loss in mice. SIRT2, a part of the SIRT family, was positively associated with NAMPT actions in human GF. Furthermore, in vivo inhibition of the NAMPT-NAD+-SIRT axis by NIC injection in mice ameliorated the periodontal inflammation and alveolar bone erosion caused by intragingival injection of Ad-Nampt. Our findings indicate that NAMPT is highly upregulated in human GF, while its enzymatic activity acts as a crucial mediator of periodontal inflammation and alveolar bone destruction via regulation of COX-2, MMP1, and MMP3 levels.
Highlights
Periodontitis is a chronic inflammatory disease characterized by irreversible destruction of the periodontium and involves bacterial infection, periodontal inflammation, degradation of gum tissues and alveolar bone resorption
Upregulation of IL-6, IL-8, CCL5, PTGS2, MMP1 and MMP3 represents the severity of inflammation during periodontal disease (Figure 1a)
FK866(μM) Ad-Nampt increased the expression of the nicotinamide phosphoribosyltransferase (NAMPT) target genes PTGS2, MMP1 and MMP3 (Figure 5i). These results indicated that iNAMPT/SIRT activity, rather than effect of circulating NAMPT (eNAMPT), promotes the upregulation of PTGS2, MMP1 and MMP3 in pathogenic human Gingival fibroblasts (GF)
Summary
Periodontitis is a chronic inflammatory disease characterized by irreversible destruction of the periodontium and involves bacterial infection, periodontal inflammation, degradation of gum tissues and alveolar bone resorption. Periodontitis is mainly caused by pathogenic microorganisms, such as Porphyromonas gingivalis and Fusobacterium nucleatum.[1] Periodontal pathogens may induce tissue damage by releasing endotoxins, such as lipopolysaccharides (LPS), which have profound effects on many cell types, including fibroblasts, osteoblasts, osteoclasts, and immune cells.[2,3] Periodontopathogens elicit inflammatory responses in the periodontium characterized by the local production of proinflammatory factors. These factors include tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, cyclooxygenase (COX)-2 ( known as prostaglandin G/H synthase (PTGS) 2) and matrix-degrading proteases, including matrix metalloproteinases (MMPs), all of which infiltrate into resident cells of the periodontium.[4,5,6] Gingival connective tissue is predominantly composed of stromal cells, such as fibroblasts, and a collagen-rich extracellular matrix. GF may have an important role in the transition from health to disease
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