title: Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw.
abstract: Bacterial biofilms have emerged as potential critical triggers in the pathogenesis of bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) or BRONJ. BRONJ lesions have shown to be heavily colonized by oral bacteria, most of these difficult to cultivate and presents many clinical challenges. The purpose of this study was to characterize the bacterial diversity in BRONJ lesions and to determine host immune response. We examined tissue specimens from three cohorts (n=30); patients with periodontal disease without a history of BP therapy (Control, n=10), patients with periodontal disease having history of BP therapy but without ONJ (BP, n=5) and patients with BRONJ (BRONJ, n=15). Denaturing gradient gel electrophoresis of polymerase chain reaction (PCR)-amplified 16S rRNA gene fragments revealed less bacterial diversity in BRONJ than BP and Control cohorts. Sequence analysis detected six phyla with predominant affiliation to Firmicutes in BRONJ (71.6%), BP (70.3%) and Control (59.1%). Significant differences (P<0.05) in genera were observed, between Control/BP, Control/BRONJ and BP/BRONJ cohorts. Enzyme-linked immunosorbent assay (ELISA) results indicated that the levels of myeloperoxidase were significantly lower, whereas interleukin-6 and tumor necrosis factor-alpha levels were moderately elevated in BRONJ patients as compared to Controls. PCR array showed significant changes in BRONJ patients with downregulation of host genes, such as nucleotide-binding oligomerization domain containing protein 2, and cathepsin G, the key modulators for antibacterial response and upregulation of secretory leukocyte protease inhibitor, proteinase 3 and conserved helix-loop-helix ubiquitous kinase. The results suggest that colonization of unique bacterial communities coupled with deficient innate immune response is likely to impact the pathogenesis of ONJ.
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, USA.
authors.forename: Smruti
authors.initials: S
authors.lastname: Pushalkar
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York, USA.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Kurago
authors.affiliation: Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York, USA.
authors.forename: Lalitha V
authors.initials: LV
authors.lastname: Ramanathapuram
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, USA.
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Fleisher
authors.affiliation: Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Glickman
authors.affiliation: Department of Biology, Nyack College, New York, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, USA.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Saxena
mesh_terms: D039903:Actinobacteria / Q000145:classification; D001419:Bacteria / Q000145:classification; D041963:Bacteroidetes / Q000145:classification; D018441:Biofilms; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000276:immunology / Q000382:microbiology*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D056649:Cathepsin G / Q000032:analysis; D015331:Cohort Studies; D015536:Down-Regulation; D005260:Female; D045182:Fusobacteria / Q000145:classification; D006090:Gram-Negative Bacteria / Q000145:classification; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D051550:I-kappa B Kinase / Q000032:analysis; D007113:Immunity, Innate / Q000276:immunology*; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009055:Mouth / Q000276:immunology / Q000382:microbiology*; D053146:Myeloblastin / Q000032:analysis / Q000037:antagonists & inhibitors; D053473:Nod2 Signaling Adaptor Protein / Q000032:analysis; D010510:Periodontal Diseases / Q000382:microbiology; D009195:Peroxidase / Q000032:analysis; D020560:Proteobacteria / Q000145:classification; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D050071:Bone Density Conservation Agents; C508600:IL6 protein, human; D015850:Interleukin-6; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C534094:CTSG protein, human; D056649:Cathepsin G; D053146:Myeloblastin
references.citation: J Oncol Pract. 2006 Jan;2(1):7-14
references.pmid: 20871729
references.citation: BMC Genomics. 2012 Jul 28;13:345
references.pmid: 22839737
references.citation: J Cell Sci. 2009 Oct 1;122(Pt 19):3522-30
references.pmid: 19759286
references.citation: Appl Environ Microbiol. 2006 Jul;72(7):5069-72
references.pmid: 16820507
references.citation: Trends Microbiol. 2003 Dec;11(12):570-7
references.pmid: 14659689
references.citation: J Oral Maxillofac Surg. 2012 Dec;70(12):2802-8
references.pmid: 22520563
references.citation: Curr Osteoporos Rep. 2010 Mar;8(1):40-8
references.pmid: 20425090
references.citation: Int J Oral Maxillofac Surg. 2010 Nov;39(11):1097-102
references.pmid: 20817480
references.citation: Science. 1988 Aug 5;241(4866):708-12
references.pmid: 3041594
references.citation: J Oral Pathol Med. 2006 Mar;35(3):155-60
references.pmid: 16454811
references.citation: Med Hypotheses. 2011 Aug;77(2):214-5
references.pmid: 21570775
references.citation: Infect Immun. 2005 Mar;73(3):1271-4
references.pmid: 15731023
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Nov;108(5):738-46
references.pmid: 19748292
references.citation: Haematologica. 2006 Sep;91(9):1165-71
references.pmid: 16956814
references.citation: Clin Microbiol Infect. 2014 May;20(5):O309-17
references.pmid: 24112138
references.citation: Anticancer Res. 2013 May;33(5):1793-7
references.pmid: 23645723
references.citation: Lancet. 2001 Jul 14;358(9276):135-8
references.pmid: 11463434
references.citation: Int J Oral Maxillofac Surg. 2013 May;42(5):619-26
references.pmid: 23578802
references.citation: J Clin Invest. 2008 Jul;118(7):2438-47
references.pmid: 18568075
references.citation: J Mater Sci Mater Med. 2005 Apr;16(4):283-7
references.pmid: 15803271
references.citation: J Leukoc Biol. 2005 May;77(5):598-625
references.pmid: 15689384
references.citation: Anaerobe. 2010 Feb;16(1):38-42
references.pmid: 19351562
references.citation: J Clin Microbiol. 2007 Jan;45(1):81-7
references.pmid: 17079495
references.citation: J Oral Maxillofac Surg. 2011 Feb;69(2):362-80
references.pmid: 21122968
references.citation: Med Hypotheses. 2012 Feb;78(2):315-8
references.pmid: 22136947
references.citation: Bone. 2009 Jan;44(1):173-5
references.pmid: 18849018
references.citation: Bone. 2009 Nov;45(5):843-52
references.pmid: 19631301
references.citation: J Dent Res. 2008 Mar;87(3):278-82
references.pmid: 18296614
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol. 2013 Jan;115(1):71-8
references.pmid: 23217537
references.citation: J Natl Cancer Inst. 2011 Feb 2;103(3):232-40
references.pmid: 21189409
references.citation: Ultrastruct Pathol. 2010 Aug;34(4):207-13
references.pmid: 20594040
references.citation: J Dent Res. 1989 May;68(5):750-60
references.pmid: 2654229
references.citation: Expert Rev Anti Infect Ther. 2010 Dec;8(12):1441-50
references.pmid: 21133668
references.citation: Microbiol Mol Biol Rev. 2002 Sep;66(3):486-505, table of contents
references.pmid: 12209001
references.citation: Oral Dis. 2009 Nov;15(8):527-37
references.pmid: 19619192
references.citation: Immunol Invest. 2006;35(2):167-79
references.pmid: 16698675
references.citation: J Craniomaxillofac Surg. 2008 Mar;36(2):95-103
references.pmid: 18234504
references.citation: Cancer. 2005 Jul 1;104(1):83-93
references.pmid: 15929121
references.citation: Microbiol Immunol. 2001;45(1):29-37
references.pmid: 11270604
references.citation: Bone. 2009 Jan;44(1):4-10
references.pmid: 18948230
references.citation: Nat Rev Rheumatol. 2011 Nov 29;8(2):90-6
references.pmid: 22124271
references.citation: Nat Rev Immunol. 2013 May;13(5):321-35
references.pmid: 23618829
references.citation: J Oral Maxillofac Surg. 2010 Apr;68(4):797-804
references.pmid: 20307765
references.citation: J Oral Maxillofac Surg. 2009 May;67(5 Suppl):61-70
references.pmid: 19371816
references.citation: Oral Oncol. 2001 Dec;37(8):613-9
references.pmid: 11590070
references.citation: J Bacteriol. 2010 Oct;192(19):5002-17
references.pmid: 20656903
references.citation: PLoS One. 2012;7(6):e37919
references.pmid: 22675498
references.citation: J Oral Maxillofac Surg. 2008 Apr;66(4):767-75
references.pmid: 18355603
references.citation: Oral Dis. 2012 Jan;18(1):85-95
references.pmid: 21883710
references.citation: J Cancer Res Clin Oncol. 2010 Aug;136(8):1117-24
references.pmid: 20508948
references.citation: Bone. 2010 Jul;47(1):127-30
references.pmid: 20399289
references.citation: Oral Dis. 2012 Sep;18(6):602-12
references.pmid: 22443347
references.citation: Am J Pathol. 1975 Jan;78(1):71-100
references.pmid: 1109560
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol. 2013 Feb;115(2):224-32
references.pmid: 23246224
references.citation: Int J Syst Evol Microbiol. 2006 Apr;56(Pt 4):751-754
references.pmid: 16585688
references.citation: J Am Dent Assoc. 2009 Oct;140(10):1259-65
references.pmid: 19797556
references.citation: BMC Microbiol. 2012 Jul 20;12:144
references.pmid: 22817758
references.citation: Clin Oral Investig. 2010 Jun;14(3):271-84
references.pmid: 19536569
references.citation: Clin Infect Dis. 1993 Jun;16 Suppl 4:S203-10
references.pmid: 8324120
references.citation: J Oral Maxillofac Surg. 2012 Jul;70(7):1587-92
references.pmid: 22177825
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Dec;114(6):764-70
references.pmid: 23159114
references.citation: J Oral Maxillofac Surg. 2009 May;67(5 Suppl):2-12
references.pmid: 19371809
references.citation: Autoimmun Rev. 2009 Dec;9(2):67-81
references.pmid: 19716440