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

Journal of Translational Medicine

Dieter Kabelitz⁴  John F Baines²  Jörg Wiltfang¹  Jörn Huck¹  Elgar Susanne Quabius³  Jun Wang²  Shirin Kalyan⁴ 

[1] Department of Oral and Maxillofacial Surgery, Christian-Albrechts University Kiel, Arnold-Heller-Str. 3, Bldg. 26, Kiel, 24105, Germany;Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Arnold-Heller-Str. 3, Bldg. 17, Kiel, 24105, Germany;Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts University Kiel, Arnold-Heller-Str. 3, Bldg. 27, Kiel, 24105, Germany;Institute of Immunology, Christian-Albrechts University Kiel, Arnold-Heller-Strasse 3, Bldg. 17, Kiel, 24105, Germany

关键词: Osteonecrosis of the jaw;    Oral microbiome;    Immune function;    Bisphosphonates;    Adverse drug effects;   

Others  :  1221476
DOI  :  10.1186/s12967-015-0568-z

 received in 2015-02-19, accepted in 2015-06-09,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Kalyan et al.

【 图 表 】

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【 参考文献 】

• [1]Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W et al.. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006; 38:617-627.
• [2]van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun. 1999; 264:108-111.
• [3]Keller RK, Fliesler SJ. Mechanism of aminobisphosphonate action: characterization of alendronate inhibition of the isoprenoid pathway. Biochem Biophys Res Commun. 1999; 266:560-563.
• [4]Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des. 2003; 9:2643-2658.
• [5]Gatti D, Adami S. New bisphosphonates in the treatment of bone diseases. Drugs Aging. 1999; 15:285-296.
• [6]Cremers SC, Pillai G, Papapoulos SE. Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet. 2005; 44:551-570.
• [7]Palaska PK, Cartsos V, Zavras AI. Bisphosphonates and time to osteonecrosis development. Oncologist. 2009; 14:1154-1166.
• [8]Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D et al.. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007; 22:1479-1491.
• [9]Wimalawansa SJ. Insight into bisphosphonate-associated osteomyelitis of the jaw: pathophysiology, mechanisms and clinical management. Expert Opin Drug Saf. 2008; 7:491-512.
• [10]Reid IR. Osteonecrosis of the jaw: who gets it, and why? Bone. 2009; 44:4-10.
• [11]Taylor KH, Middlefell LS, Mizen KD. Osteonecrosis of the jaws induced by anti-RANK ligand therapy. Br J Oral Maxillofac Surg. 2010; 48:221-223.
• [12]Edwards BJ, Gounder M, McKoy JM, Boyd I, Farrugia M, Migliorati C et al.. Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw. Lancet Oncol. 2008; 9:1166-1172.
• [13]Kalyan S, Quabius ES, Wiltfang J, Monig H, Kabelitz D. Can peripheral blood gammadelta T cells predict osteonecrosis of the jaw? An immunological perspective on the adverse drug-effects of aminobisphosphonate therapy. J Bone Miner Res. 2013; 28:728-735.
• [14]Kalyan S, Chandrasekaran V, Quabius ES, Lindhorst TK, Kabelitz D. Neutrophil uptake of nitrogen-bisphosphonates leads to the suppression of human peripheral blood gammadelta T cells. Cell Mol Life Sci. 2013; 71:2335-2346.
• [15]Kalyan S, Kabelitz D. When neutrophils meet T cells: beginning of a tumultuous relationship with underappreciated potential. Eur J Immunol. 2014; 44:627-633.
• [16]Sabbione F, Gabelloni ML, Ernst G, Gori MS, Salamone G, Oleastro M. Neutrophils suppress γδ T-cell function. Eur J Immunol. 2014; 44:819-830.
• [17]Deetz CO, Hebbeler AM, Propp NA, Cairo C, Tikhonov I, Pauza CD. Gamma interferon secretion by human Vgamma2 Vdelta2 T cells after stimulation with antibody against the T-cell receptor plus the Toll-Like receptor 2 agonist Pam3Cys. Infect Immun. 2006; 74:4505-4511.
• [18]Workalemahu G, Foerster M, Kroegel C. Expression and synthesis of fibroblast growth factor-9 in human gammadelta T-lymphocytes. Response to isopentenyl pyrophosphate and TGF-beta1/IL-15. J Leukoc Biol. 2004; 75:657-663.
• [19]Workalemahu G, Foerster M, Kroegel C, Braun RK. Human gamma delta-T lymphocytes express and synthesize connective tissue growth factor: effect of IL-15 and TGF-beta 1 and comparison with alpha, beta-T lymphocytes. J Immunol. 2003; 170:153-157.
• [20]Workalemahu G, Foerster M, Kroegel C. Expression of metalloproteinase-7 (matrilysin) in human blood and bronchoalveolar gamma/delta T-lymphocytes. Selective upregulation by the soluble non-peptidic mycobacterial phosphoantigen (isopentenyl pyrophosphate). J Cell Physiol. 2006; 207:67-74.
• [21]Kress E, Hedges JF, Jutila MA. Distinct gene expression in human Vdelta1 and Vdelta2 gammadelta T cells following non-TCR agonist stimulation. Mol Immunol. 2006; 43:2002-2011.
• [22]Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF et al.. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell. 2011; 147:629-640.
• [23]Roberts NA, White AJ, Jenkinson WE, Turchinovich G, Nakamura K, Withers DR et al.. Rank signaling links the development of invariant gammadelta T cell progenitors and Aire(+) medullary epithelium. Immunity. 2012; 36:427-437.
• [24]Lukens JR, Barr MJ, Chaplin DD, Chi H, Kanneganti TD. Inflammasome-derived IL-1beta regulates the production of GM-CSF by CD4(+) T cells and gammadelta T cells. J Immunol. 2012; 188:3107-3115.
• [25]Mawardi H, Giro G, Kajiya M, Ohta K, Almazrooa S, Alshwaimi E et al.. A role of oral bacteria in bisphosphonate-induced osteonecrosis of the jaw. J Dent Res. 2011; 90:1339-1345.
• [26]Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW. Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg. 2008; 66:767-775.
• [27]Boff RC, Salum FG, Figueiredo MA, Cherubini K. Important aspects regarding the role of microorganisms in bisphosphonate-related osteonecrosis of the jaws. Arch Oral Biol. 2014; 59:790-799.
• [28]Allen MR, Burr DB. The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg. 2009; 67:61-70.
• [29]Ji X, Pushalkar S, Li Y, Glickman R, Fleisher K, Saxena D. Antibiotic effects on bacterial profile in osteonecrosis of the jaw. Oral Dis. 2012; 18:85-95.
• [30]Montefusco V, Gay F, Spina F, Miceli R, Maniezzo M, Teresa Ambrosini M et al.. Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates. Leuk Lymphoma. 2008; 49:2156-2162.
• [31]Pfeilschifter J. 2006 DVO-guideline for prevention, diagnosis, and therapy of osteoporosis for women after menopause, for men after age 60 executive summary guidelines. Exp Clin Endocrinol Diabetes. 2006; 114:611-622.
• [32]Nolan T, Hands RE, Bustin SA. Quantification of mRNA using real-time RT-PCR. Nat Protoc. 2006; 1:1559-1582.
• [33]Linnenbrink M, Wang J, Hardouin EA, Kunzel S, Metzler D, Baines JF. The role of biogeography in shaping diversity of the intestinal microbiota in house mice. Mol Ecol. 2013; 22:1904-1916.
• [34]Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB et al.. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol. 2009; 75:7537-7541.
• [35]Hamady M, Knight R. Microbial community profiling for human microbiome projects: tools, techniques, and challenges. Genome Res. 2009; 19:1141-1152.
• [36]Edgar RC, Haas BJ, Clemente JC, Quince C, Knight R. UCHIME improves sensitivity and speed of chimera detection. Bioinformatics. 2011; 27:2194-2200.
• [37]Wang Q, Garrity GM, Tiedje JM, Cole JR. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol. 2007; 73:5261-5267.
• [38]Anderson MJ, Willis TJ. Canonical analysis of prinicpal coordinates: a useful method of constrained ordination for ecology. Ecology. 2003; 84:511-525.
• [39]Oksanen J, Blanchet GF, Kindt R, Legendre P, Minchin RP, O’Hara RB et al. vegan: Community Ecology Package. R Package Version 2.0-2. (http://CRAN.R-project.org/package=vegan)
• [40]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001; 25:402-408.
• [41]Kunzmann V, Bauer E, Wilhelm M. Gamma/delta T-cell stimulation by pamidronate. N Engl J Med. 1999; 340:737-738.
• [42]Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003; 61:1115-1117.
• [43]Badros A, Terpos E, Katodritou E, Goloubeva O, Kastritis E, Verrou E et al.. Natural history of osteonecrosis of the jaw in patients with multiple myeloma. J Clin Oncol. 2008; 26:5904-5909.
• [44]Kalyan S, Huebbe P, Esatbeyoglu T, Niklowitz P, Cote HC, Rimbach G et al.. Nitrogen-bisphosphonate therapy is linked to compromised coenzyme Q10 and vitamin E status in postmenopausal women. J Clin Endocrinol Metab. 2014; 99:1307-1313.
• [45]Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med. 2006; 12:17-25.
• [46]Wong BR, Josien R, Lee SY, Sauter B, Li HL, Steinman RM et al.. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med. 1997; 186:2075-2080.
• [47]Vogel CF, Wu D, Goth SR, Baek J, Lollies A, Domhardt R et al.. Aryl hydrocarbon receptor signaling regulates NF-kappaB RelB activation during dendritic-cell differentiation. Immunol Cell Biol. 2013; 91:568-575.
• [48]Wang CK, Chang H, Chen PH, Chang JT, Kuo YC, Ko JL et al.. Aryl hydrocarbon receptor activation and overexpression upregulated fibroblast growth factor-9 in human lung adenocarcinomas. Int J Cancer. 2009; 125:807-815.
• [49]Quarto N, Behr B, Li S, Longaker MT. Differential FGF ligands and FGF receptors expression pattern in frontal and parietal calvarial bones. Cells Tissues Organs. 2009; 190:158-169.
• [50]Wei X, Pushalkar S, Estilo C, Wong C, Farooki A, Fornier M et al.. Molecular profiling of oral microbiota in jawbone samples of bisphosphonate-related osteonecrosis of the jaw. Oral Dis. 2012; 18:602-612.
• [51]Pushalkar S, Li X, Kurago Z, Ramanathapuram LV, Matsumura S, Fleisher KE et al.. Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw. Int J Oral Sci. 2014; 6:219-226.
• [52]Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 2011; 364:656-665.