title: 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: OBJECTIVE
  We have previously shown that the secreted glycoprotein milk fat globule epidermal growth factor 8 (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.
  
  
  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 analysed 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.
  
  
  CONCLUSIONS
  MFG-E8 is, in principle, a novel therapeutic agent and biomarker of periodontitis.
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Kajikawa
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Fatimah
authors.identifier: http://orcid.org/0000-0003-4715-1538
authors.initials: F
authors.lastname: Meshikhes
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: Department of Preventive and Restorative Sciences, Division of Pediatric Dentistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Evlambia
authors.initials: E
authors.lastname: Hajishengallis
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Kavita B
authors.initials: KB
authors.lastname: Hosur
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Dental Ecology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Moss
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: George
authors.identifier: http://orcid.org/0000-0001-7392-8852
authors.initials: G
authors.lastname: Hajishengallis
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D055113:Chronic Periodontitis / Q000175:diagnosis* / Q000378:metabolism / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D005883:Gingival Crevicular Fluid / Q000378:metabolism*; D005891:Gingivitis / Q000175:diagnosis / Q000378:metabolism / Q000628:therapy; D006801:Humans; D008252:Macaca fascicularis; D008894:Milk Proteins / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000954:Antigens, Surface; D015415:Biomarkers; C098942:MFGE8 protein, human; D008894:Milk Proteins
keywords: cytokines; inflammation; milk fat globule epidermal growth factor 8; non-human primates; periodontitis