title: Systemic immunity shapes the oral microbiome and susceptibility to bisphosphonate-associated osteonecrosis of the jaw.
abstract: BACKGROUND
  Osteonecrosis of the jaw (ONJ) is a rare but serious adverse drug effect linked to long-term and/or high-dose exposure to nitrogen-bisphosphonates (N-BP), the standard of care for the treatment of bone fragility disorders. The mechanism leading to bisphosphonate-associated ONJ (BAONJ) is unclear and optimal treatment strategies are lacking. Recent evidence suggests that BAONJ may be linked to drug-induced immune dysfunction, possibly associated with increased susceptibility to infections in the oral cavity. The objective of this investigation was to comprehensively assess the relationship linking immune function, N-BP exposure, the oral microbiome and ONJ susceptibility.
  
  
  METHODS
  Leukocyte gene expression of factors important for immunity, wound healing and barrier function were assessed by real-time quantitative PCR and the oral microbiome was characterized by 454 pyrosequencing of the 16S rRNA gene in 93 subjects stratified by N-BP exposure and a history of ONJ.
  
  
  RESULTS
  There were marked differences in the systemic expression of genes regulating immune and barrier functions including RANK (p = 0.007), aryl hydrocarbon receptor (AHR, p < 0.001), and FGF9 (p < 0.001), which were collectively up-regulated in individuals exposed to N-BP without ONJ relative to treatment controls. In contrast, the expression levels of these same genes were significantly down-regulated in those who had experienced BAONJ. Surprisingly, the oral microbiome composition was not directly linked to either BAONJ or N-BP exposure, rather the systemic leukocyte expression levels of RANK, TNFA and AHR each explained 9% (p = 0.04), 12% (p = 0.01), and 7% (p = 0.03) of the oral bacterial beta diversity.
  
  
  CONCLUSIONS
  The oral microbiome is unlikely causative of ONJ, rather individuals with BAONJ lacked immune resiliency which impaired their capacity to respond adequately to the immunological stress of N-BP treatment. This may be the common factor linking N-BP and anti-RANK agents to ONJ in at-risk individuals. Preventive and/or therapeutic strategies should target the wound healing deficits present in those with ONJ.
authors.affiliation: Institute of Immunology, Christian-Albrechts University Kiel, Arnold-Heller-Strasse 3, Bldg. 17, 24105, Kiel, Germany. shirin.kalyan@ubc.ca.
authors.forename: Shirin
authors.initials: S
authors.lastname: Kalyan
authors.affiliation: Max Planck Institute for Evolutionary Biology, August-Thienemann-Str. 2, 24306, Plön, Germany. wang@evolbio.mpg.de.|Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Arnold-Heller-Str. 3, Bldg. 17, 24105, Kiel, Germany. wang@evolbio.mpg.de.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Immunology, Christian-Albrechts University Kiel, Arnold-Heller-Strasse 3, Bldg. 17, 24105, Kiel, Germany. ElgarSusanne.Quabius@uksh.de.|Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts University Kiel, Arnold-Heller-Str. 3, Bldg. 27, 24105, Kiel, Germany. ElgarSusanne.Quabius@uksh.de.
authors.forename: Elgar Susanne
authors.initials: ES
authors.lastname: Quabius
authors.affiliation: Department of Oral and Maxillofacial Surgery, Christian-Albrechts University Kiel, Arnold-Heller-Str. 3, Bldg. 26, 24105, Kiel, Germany. huck@mkg.uni-kiel.de.
authors.forename: Jörn
authors.initials: J
authors.lastname: Huck
authors.affiliation: Department of Oral and Maxillofacial Surgery, Christian-Albrechts University Kiel, Arnold-Heller-Str. 3, Bldg. 26, 24105, Kiel, Germany. wiltfang@mkg.uni-kiel.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Wiltfang
authors.affiliation: Max Planck Institute for Evolutionary Biology, August-Thienemann-Str. 2, 24306, Plön, Germany. baines@evolbio.mpg.de.|Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Arnold-Heller-Str. 3, Bldg. 17, 24105, Kiel, Germany. baines@evolbio.mpg.de.
authors.forename: John F
authors.initials: JF
authors.lastname: Baines
authors.affiliation: Institute of Immunology, Christian-Albrechts University Kiel, Arnold-Heller-Strasse 3, Bldg. 17, 24105, Kiel, Germany. dietrich.kabelitz@uksh.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
mesh_terms: D000368:Aged; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*; D004164:Diphosphonates / Q000009:adverse effects; D004198:Disease Susceptibility / Q000276:immunology / Q000382:microbiology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007109:Immunity; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D064307:Microbiota / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D009055:Mouth / Q000382:microbiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics
chemical_list: D004164:Diphosphonates; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018336:Receptors, Aryl Hydrocarbon; C505686:TNFRSF11A protein, human