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  Systemic immunity shapes the oral microbiome and susceptibility to bisphosphonate‑associated osteonecrosis of the jaw

Kalyan, S., Wang, J., Quabius, E. S., Huck, J., Wiltfang, J., Baines, J. F., et al. (2015). Systemic immunity shapes the oral microbiome and susceptibility to bisphosphonate‑associated osteonecrosis of the jaw. Journal of Translational Medicine, 13(212). doi:10.1186/s12967-015-0568-z.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-F88C-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-F88D-9
Genre: Journal Article

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 Creators:
Kalyan, Shirin, Author
Wang, Jun1, Author              
Quabius, Elgar Susanne, Author
Huck, Jörn, Author
Wiltfang, Jörg, Author
Baines, John F.1, Author              
Kabelitz, Dieter, Author
Affiliations:
1Guest Group Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445638              

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Free keywords: Adverse drug effects; Bisphosphonates; Immune function; Oral microbiome; 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.

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Language(s): eng - English
 Dates: 2015-02-192015-06-092015-07-04
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1186/s12967-015-0568-z
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Title: Journal of Translational Medicine
Source Genre: Journal
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Publ. Info: London : BioMed Central
Pages: 13 S. Volume / Issue: 13 (212) Sequence Number: - Start / End Page: - Identifier: ISSN: 1479-5876
CoNE: /journals/resource/111061240938000