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: Shirin Kalyan, Jun Wang, Elgar Susanne Quabius, Jörn Huck, Jörg Wiltfang, John F Baines, Dieter Kabelitz
• Journal: Journal of translational medicine (J Transl Med) Vol. 13 Pg. 212 (Jul 04 2015) ISSN: 1479-5876 [Electronic] England
• PMID: 26141514 (Publication Type: Journal Article)

Chemical References

• Diphosphonates
• RNA, Messenger
• Receptor Activator of Nuclear Factor-kappa B
• Receptors, Aryl Hydrocarbon
• TNFRSF11A protein, human

Topics

• Aged
• Bisphosphonate-Associated Osteonecrosis of the Jaw (genetics, immunology, microbiology)
• Diphosphonates (adverse effects)
• Disease Susceptibility (immunology, microbiology)
• Female
• Gene Expression Regulation
• Humans
• Immunity
• Leukocytes (metabolism)
• Male
• Microbiota (genetics, immunology)
• Middle Aged
• Mouth (microbiology)
• RNA, Messenger (genetics, metabolism)
• Receptor Activator of Nuclear Factor-kappa B (metabolism)
• Receptors, Aryl Hydrocarbon (genetics, metabolism)
• Wound Healing (genetics)