Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw
Authors: Smruti Pushalkar, Xin Li, Zoya Kurago, Lalitha V Ramanathapuram, Satoko Matsumura, Kenneth E Fleisher, Robert Glickman, Wenbo Yan, Yihong Li, Deepak Saxena
Journal: International Journal of Oral Science (2014)

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. Decreased immune response and colonization by certain bacteria may increase risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Deepak Saxena of the New York University College of Dentistry, USA, and colleagues have shown that cancer patients who have been treated with bisphosphonates to reduce bone loss can, paradoxically, experience localized bone loss from the jaw. In a study of 30 oral surgery patients, Saxena and colleagues used a genetic approach to identify oral bacteria in BRONJ lesions and compared the immune responses of BRONJ patients and controls. BRONJ patients showed decreased immune response and more frequent colonization by opportunistic pathogens such as Parvimonas, Fusobacterium, Eubacterium besides, Streptococcus onto the BP-bound bone contributing to jaw necrosis. Some unnamed or uncultured bacteria were only found in BRONJ and bisphosphonate-treated patients. This study of the relationship between microbial colonization and immune response provides insights into the disease process in BRONJ.