Milk fat globule epidermal growth factor 8 inhibits periodontitis in non‐human primates and its gingival crevicular fluid levels can differentiate periodontal health from disease in humans

Abstract

Aim We have previously shown that the secreted glycoprotein MFG-E8 has anti-inflammatory and anti-osteoclastogenic properties. Our objective was to investigate the potential of MFG-E8 as a diagnostic or therapeutic agent in periodontitis. Materials and Methods Periodontitis was induced in non-human primates (NHPs) by placing ligatures around posterior teeth on both halves of the mandible for a split-mouth design: one side was treated with MFG-E8−Fc and the other with Fc control. Disease was assessed by clinical periodontal examinations, radiographic analysis of bone loss, and analysis of cytokine mRNA expression in gingival biopsy samples. Gingival crevicular fluid (GCF) was collected from human healthy volunteers or subjects with gingivitis, chronic moderate periodontitis, or chronic severe periodontitis. Additionally, GCF was collected from a subset of severe periodontitis patients following scaling and root planing (SRP) and after pocket reduction surgery. GCF was analyzed to quantify MFG-E8 and periodontitis-relevant cytokines using multiplex assays. Results In NHPs, sites treated with MFG-E8-Fc exhibited significantly less ligature-induced periodontal inflammation and bone loss than Fc control-treated sites. In humans, the GCF levels of MFG-E8 were significantly higher in health than in periodontitis, whereas the reverse was true for the proinflammatory cytokines tested. Consistently, MFG-E8 was elevated in GCF after both non-surgical (SRP) and surgical periodontal treatment of periodontitis patients. Conclusion MFG-E8 is, in principle, a novel therapeutic agent and biomarker of periodontitis.

DEL-1 promotes macrophage efferocytosis and clearance of inflammation

“…Periodontitis, in which neutrophils play a major pathogenic role19, is a pathology amenable to studies of resolution of inflammation20. Resolution of inflammation in human periodontitis correlates with reduction in the amount of inflammatory mediators ( e.g ., IL-6 and IL-17) in the fluid exudate adjacent to periodontitis inflamed lesions (gingival crevicular fluid; GCF)21. We found that DEL-1 protein is significantly elevated in the GCF upon treatment of periodontitis by mechanical debridement (scaling and root planing, SRP), which leads to clinical inflammatory resolution22, as also confirmed here by assessing probing pocket depth (PPD), a parameter that measures inflammatory tissue destruction (Supplementary Fig.…”

Current understanding of periodontal disease pathogenesis and targets for host‐modulation therapy

“…At the C‐terminus, both developmental endothelial locus‐1 and milk fat globule‐epidermal growth factor‐8 have 2 discoidin I‐like domains which can bind phospholipids and glycosaminoglycans . Both proteins were shown to have important homeostatic functions and to inhibit periodontitis in mouse and nonhuman primate models …”

DEL-1-Regulated Immune Plasticity and Inflammatory Disorders

“…This finding suggested that DEL-1 expression might resurge during resolution, which could be partially attributed to the rising levels of resolvins. Indeed, DEL-1 protein concentrations were significantly elevated in the gingival crevicular fluid of periodontitis patients upon treatment (mechanical debridement to remove the pathogenic biofilm), which led to clinical inflammatory resolution [13,65]. Similarly, DEL-1 mRNA and protein expression is also upregulated during the resolution of murine periodontal inflammation [13].…”